Implant compositions for the unidirectional delivery of therapeutic compounds to the brain

ABSTRACT

The present invention provides, in some aspects, bilayered and trilayered pharmaceutical implant compositions for the unidirectional delivery of anti-cancer compounds to the brain over a period of time (e.g., several weeks, 1, 2, 3, 4, 5, 6, 7 days, or 1, 2, 3, weeks, or any range derivable therein) following the removal of glioblastoma multiforme or other malignant tumors in the brain.

This application is a divisional of U.S. application Ser. No.15/928,057, filed Mar. 21, 2018, which is a divisional of U.S.application Ser. No. 15/221,827, filed Jul. 28, 2016, now U.S. Pat. No.9,956,172, which claims the benefit of U.S. Provisional PatentApplication No. 62/197,739, filed Jul. 28, 2015, U.S. Provisional PatentApplication No. 62/198,040, filed Jul. 28, 2015, and U.S. ProvisionalPatent Application No. 62/329,973, filed Apr. 29, 2016, the entirety ofeach of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates generally to the field of pharmaceuticsand medicine. More particularly, it concerns pharmaceutical implants fordrug delivery and methods of use thereof.

2. Description of Related Art

There have been many therapeutic methods developed to treat braincancer, including surgery, radiotherapy and chemotherapy. The presentinvention relates to pharmaceutical compositions that have activity asanti-cancer agents and to the methods for the treatment of cancer inpatients.

Glioblastoma Multiforme is a grade 4 astrocytoma. It is an aggressivecancer that grows from the supportive cells in the brain and isdiffusely infiltrative. The current standard treatment is aggressivesurgical debulking followed by combined modality therapy of chemotherapyand radiation. Despite the neurosurgeon successfully resecting allvisible abnormal tissue during surgery, there are normally many cancercells that extend well past the resection cavity and are still presentin the patient after the surgery. The average survival rate for patientswith glioblastoma multiforme who have had aggressive treatments,including surgical resection, radiotherapy and chemotherapy, has beenreported to be about fourteen months. It has also been reported thatless than 30% of patients survive two years. Long-term survival isextremely rare.

Billions of dollars have been spent over the past 30 years on newtherapies with survival benefits only increasing on the scale of months,not years, and presently no curative therapies exist. Outside ofstandard chemotherapeutics, antiangiogenics have shown only minimalbenefit. Currently, researchers are working on individualized therapybased on specific genetic mutations of a patient's individual tumor.Vaccines are being developed to combat some of these mutations. Localchemotherapy at the tumor resection site has also been attempted withsome minimal degree of success. From a scientific standpoint, trialshave shown statistically significant survival improvements, but asurvival expectation of 15 months rather than 13 months may representonly a very modest improvement for the patient. Although researchershave successfully cured cancer in some animal models, this success hasrarely been duplicated in humans with glioblastoma.

A variety of biodegradable polymers, including the polyesters andpolyanhydrides have been reported in the literature as carrier polymersfor anti-cancer compounds. Of these materials, polylactide-co-glycolicacid (PLGA) has been extensively studied. However, although variousbiodegradable polymeric materials have been tested for drug delivery,relatively few commercial products that have reached the marketplaceutilize either polyesters or polyanhydrides.

One such product that has been marketed is the Gliadel® wafer implantthat contains carmustine for the treatment of malignant gliomas.Gliadel® has been on the market for almost twenty years and is the onlyFDA approved local implant to treat glioblastoma multiforme. There arepresently no generic equivalents on the market. The polyanhydridecarrier in the Gliadel® implants is a co-polymer, polifeposan, whichconsists of 1,3-bis(p-carboxyphenoxy) propane and sebacic acid in amolar ratio of 80 to 20. Molecules of active ingredient are distributedthrough the polymer matrix, which controls drug delivery at the site ofthe implant. The product is designed to deliver therapeutic levels ofthe drug that cannot be achieved with other routes of drug delivery,including i.v. and oral. It has been reported that the median survivalof patients with Gliadel® wafers for recurrent glioblastoma wasthirty-one weeks compared to twenty-three weeks for those on placebo,although this was not statistically significant. Survival benefit wasindeed statistically significant in patients with newly diagnosedglioblastoma, although the benefit is deemed as modest by most (˜2months).

The increase in side effects such as seizures, wound healingdifficulties, the development of cysts, and reactive brain edema seenwith the Gliadel® wafers has been a major concern to neurosurgeonswishing to use this product on their patients. Up to eight wafers can beimplanted in a patient following removal of the tumor. There have beenreports where some neurosurgeons have re-operated to remove these wafersfrom patients due to severe adverse side effects.

Several theories have been proposed regarding the reasons for increasedside effects and toxicity of the Gliadel® wafers in patients whencompared to a placebo. For implants based on the biodegradablepolyesters and polyanhydrides, there is a potential for toxicity fromdose dumping (burst effect), inconsistent drug release and the breakdownof the polymer from hydrolysis or enzymatic degradation. The by-productsof polyanhydride polymer degradation include the formation of carboxylicacids amongst other byproducts. The presence of agents to preventoxidation of the polymer in the solid state may also contribute to theseside effects. Irritation at the cellular level by these low molecularweight degradation compounds may be one of the causes of toxic sideeffects. Slight variations in the molecular weight of the polymer mayalso result in higher levels of low molecular weight fractions, whichwill biodegrade faster than the higher molecular weight fractions in thepolymeric carrier. Acidic by-products can also be generated duringstorage of the polymers, which may influence the long term chemicalstability of the biologically active compound. Since thesepolyanhydrides are soluble in most organic solvents, the incorporationof a therapeutic agent into such polymers generally occurs using anorganic solvent which dissolves the polymer and often times theanticancer compound, prior to the evaporation of the solvent to form thefinished delivery system. These organic solvents used to dissolve thepolymers include dichloromethane, acetone, tetrahydrofuran, and ethylacetate and residual solvents in these polymeric devices have their owninherent toxicity. Dichloromethane is one of the most popular solventsreported in the literature to prepare films or wafers, microparticles,and microcapsules of drug-containing biodegradable polymericformulations. The FDA has classified dichloromethane as a Class 2solvent, which should be limited in pharmaceutical products due to itsinherent toxicity. In 2012, the limit for this solvent in apharmaceutical product was six hundred parts per million. The breakdownor erosion of a polyester or a polyanhydride based delivery system atthe site of implantation in the brain or at other sites of the body maycause the formation of particles or agglomerate of polymer that canirritate surrounding tissue, which may result in adverse side effects.

Certain problems exist for current treatments for glioblastomamultiforme. The current standard treatment for patients suffering fromglioblastoma multiforme is to begin taking oral temozolomide capsulestwo to four weeks after surgery. Radiation treatments are usuallyinitiated in a similar timeframe. The delay allows for the wound tobegin the healing process. The disadvantage of the delay is that cancercells continue to grow during this time period.

Temozolamide can also display adverse side effects. Commercial capsulesof temozolomide are available in doses ranging from 5 mg to 250 mg. Thedrug has a short biological half-life of approximately 1½ hours and thusmust be frequently administered to patients to maintain therapeuticlevels. Multiple side effects have been reported for temozolomideincluding nausea, vomiting, constipation, headache and fatigue. Theseside effects occur in greater than 30% of patients taking temozolomidecapsules. Other, less common, side effects have also been reported.Various compositions have been generated in an attempt to try to alterthe release of temozolamide, such as the tableted microspheres describedin U.S. Pat. No. 8,821,913.

Lipids have been studied for applications such as intramuscular implantsand excipients in parenterals and oral solid dosage forms; however,major problems have been observed with implants and oral tablets thatrely upon lipids to retard drug release, include erratic and incompletedrug release performance. “Tailing”, is a phenomenon, where the final15-25% of the drug remains locked in the wax matrix, resulting insubtherapeutic levels of the drug substance.

Additional efforts to generate delivery systems have also resulted invarious challenges. To resolve the erratic release properties andphysical stability issues with lipid based systems, numerous researchershave included water soluble pore forming polymers such as polyethyleneglycol in the formulation. Hydrophilic polymers have also been studiedas retardant carrier excipients in solid dosage forms, includingimplants. However, the dissolution and swelling properties of theseimplants would result in high levels of drug being released directlyinto the brain cavity over a short period of time. For implants thatdeliver anti-cancer compounds to the cavity of the brain followingsurgical removal of the tumor, drug release over a period of 1-2 dayswould be ineffective since therapeutic levels of the drug need to bemaintained over periods of weeks, not days. Furthermore, by releasingthe drug directly into the fluid of the brain cavity, the concentrationwould be low resulting in minimal diffusion of the active drug moleculesacross the surface of the cavity into the brain. In addition, the drugwould circulate to other normal portions of the central nervous system,possibly leading to side effects. Clearly, there is a need for improvedmethods and implants for the treatment of brain tumors.

SUMMARY OF THE INVENTION

The present invention overcomes limitations in the prior art byproviding, in some aspects, multilayered implants or wafers that may beused, e.g., to deliver a chemotherapeutic agent and/or a steroid to thebrain after the resection of a brain tumor. For example and as notedherein, implants of the present invention can result in a slowed releaseof a drug from the implant or wafer that may improve the therapeuticeffect of the drug; additionally, in some aspects, a hydrophobic coatingon the implant may reduce, slow, minimize, or substantially preventrelease of the drug into the cerebrospinal fluid in order to improve thetherapeutic effect of the drug (e.g., an chemotherapeutic and/or asteroid).

In some aspects of the present invention, an anti-cancer compound isformulated into a multilayered (e.g., bilayered or trilayered) waferimplant that can be delivered directly to the wall of the cavity in thebrain from where a tumor was removed, to increase survival rates incancer patients. The slow release of the drug from the implant can allowfor the absorption and distribution of the anti-cancer compound into thelocal environment of the brain to provide therapeutic levels of theactive moiety over extended time periods, e.g., to kill cancer cells inthe brain.

The composition of the drug-containing layer of the wafer implant mayinclude or comprise one or more drugs, a lipid and a hydrophilic polymerand, optionally, one or more other additives. The implant may be appliedto the inner surface of the resection cavity in the brain followingsurgical removal of the tumor. A second top layer can comprise one ormore hydrophobic agents, which can reduce, prevent, slow, or minimizethe diffusion of drug from the implant into the cerebrospinal fluid ofthe resection cavity. Through this property, this layer may promoteunidirectional absorption of drug through the inner wall in the cavity.The two layers are preferably in a side-by-side configuration. Anoptional third layer may comprise a hydrophilic polymer, e.g., tofurther enhance bioadhesiveness of the implant to the wall of theresection cavity. When the third layer is used, the drug containinglayer of the implant may preferably be sandwiched between thehydrophobic layer and the hydrophilic polymer layer. A hydrophobiccoating may be applied to all surfaces of the wafer where drug releaseis not desirable. In some embodiments, this includes the sides of thewafer and the hydrophobic layer, leaving the bioadhesive layernon-coated and therefore promoting drug release in a substantiallyunidirectional fashion. Thus, in some embodiments, anti-cancer compoundsthat are ineffective when administered via a given route ofadministration (e.g., by the oral or parenteral route) and/or havedifficulty in crossing the blood-brain barrier by the traditional routesof administration may nonetheless be administered to the brain. Forexample, various anti-cancer agents that are toxic when administered(e.g., systemically or orally) may be administered to a subject in animplant of the present invention to achieve therapeutic concentrationsin the brain. High temperature curing of these implant compositions maybe employed to increase the adhesion of both the hydrophobic andhydrophilic layers to the drug containing layer.

It has been found in various aspects of the present invention thatbiocompatible pharmaceutical wafer implant compositions comprisingbiologically active compounds to treat tumors (e.g., malignant tumors)can be prepared using lipids as inert carrier materials and hydrophilicwater soluble pore forming polymeric agents to regulate the drug releaserate. The wafers may optionally include one or more additives (e.g., toimprove processing and to control the rate of release of the activeagent from the solid dosage form; or a preservative, antibiotic, orantimicrobial agent to reduce microbial growth and/or infection). Thiscombination of ingredients in the wafer or implant may provide for acontrolled release of the anti-cancer compound(s) at the tumor site,while causing little or no change in the pH at the site of implantation.Thus, in some embodiments, the wafer or implant results in essentiallyno harmful release of byproducts to irritate the cellular linings of thesurrounding tissues.

In one aspect, the present invention relates to a biocompatible drugdelivery implant for positioning adjacent to a biological tissue fordelivering one or more drugs thereto, the implant comprising at leasttwo layers, a drug-containing layer having a drug elution surface to bepositioned proximal to the tissue, and, a further layer or layerscomprising a lipophilic backing layer and/or a hydrophobic coating, saidfurther layer or layers being positioned distal to the drug elutionsurface, wherein: a) the drug-containing layer comprises one or moredrugs, a hydrophilic polymer or pore forming agent, and a biocompatiblehydrophobic lipid or polymer; b) the lipophilic backing layer comprisesa biocompatible hydrophobic lipid or polymer; and c) the hydrophobiccoating comprises a biocompatible hydrophobic lipid or polymer and coatssurfaces of the implant that are not to be positioned proximal to thetissue and; and further, when each of layers a), b) and c) are present,the lipophilic backing layer is positioned between the drug-containinglayer and the hydrophobic coating. In some embodiments, the implantcomprises layers a) and b). In some embodiments, the implant compriseslayers a) and c). In some embodiments, the implant comprises layers a),b) and c). The implant may further comprise a drug-permeable,hydrophilic layer d) positioned between the drug elution surface of thedrug-containing layer and to be positioned proximal to the tissue. Insome embodiments, the layer d) does not contain the drug. The layer d)may contain a steroid. In some embodiments, the layer d) contains thedrug. In some embodiments, the layer d) contains a steroid and the drug.In some embodiments, the steroid is dexamethasone. In some embodiments,the hydrophobic lipid or polymer in layers a), b), and/or c) is asteroid or a fatty acid. The steroid may be a cholesterol. In someembodiments, the fatty acid is a saturated fatty acid. The saturatedfatty acid may have 6 to 24 carbon atoms or 12 to 24 carbon atoms. Thefatty acid may be stearic acid, palmitic acid, or a glyceride. In someembodiments, the glyceride contains a mixture of monoglyceride,diglyceride, and triglyceride. In some embodiments, the mixture containspredominately diglyceride. The glyceride may be a glyceryl behenate orstearin (tristearin). In some embodiments, the hydrophobic lipid isglycerol behenate, a fatty acid, a cholesterol, a glyceride, ahydrogenated vegetable oil, tristearin, or the like. In someembodiments, the hydrophilic polymer present in layer a) and/or d) is apolyether or a polysaccharide. In some embodiments, the hydrophilicpolymer is a polyethylene oxide, polypropylene oxide, or a polyethyleneglycol. In some embodiments, the hydrophilic polymer is a polyethyleneoxide or a polysaccharide. In some embodiments, the polysaccharide ischitosan or polyanhydroglucuronic acid. The hydrophilic polymer maycomprise a mixture of a polyether and a polysaccharide. In someembodiments, the hydrophilic polymer is a mixture comprisingpolyethylene oxide and chitosan. The hydrophilic polymer may bepolyethylene oxide or polyanhydroglucuronic acid. In some embodiments,the hydrophilic polymer is polyethylene oxide, chitosan, povidone (PVPor polyvinylpyrrolidone), or polyanhydroglucuronic acid. The drug may bean anti-cancer compound. The anti-cancer compound may be a chemotherapyor a chemotherapeutic agent. In some embodiments, the chemotherapeuticis temozolomide, paclitaxel, cetuximab, irinotecan, everolimus,carboplatin, or docetaxel. The drug may be cisplatin, topotecan,bevacizumab, doxorubicin, everolimus, paclitaxel, irinotecan,carboplatin, D-actinomycin, docetaxel, pitavastatin, methotrexate,temozolomide, epirubicin, cetuximab, a copper chelating agent,carmustine, a synthetic alkyl lysophospholipid, a bioactive sulfatedsaponin, steroid, or a statin. In some embodiments, the drug is asteroid. In some embodiments, layer a) comprises both a chemotherapeuticagent and a steroid. In some embodiments, layer a) comprises achemotherapeutic agent, and wherein the implant further comprises thelayer d), wherein layer d) comprises a steroid. Layer a) may furthercomprise a steroid. The steroid may be dexamethasone or dexamethasonesodium phosphate. In some embodiments, the chemotherapeutic agent istemozolomide or paclitaxel; and wherein the steroid is dexamethasone. Insome embodiments, the implant is substantially circular or elliptical inshape. In some embodiments, the implant is further defined as a wafer.The wafer or tablet may be configured for insertion into a resectioncavity. The implant or wafer may further comprise an additionaltherapeutic agent (e.g., an antibiotic, an antimicrobial agent, astatin, an anti-fungal agent, an anti-viral agent, a steroid, ananesthetic, a local anesthetic, or a NSAID). In some embodiments, theadditional therapeutic agent is an antibiotic or an antimicrobial agent.In some embodiments, the implant does not contain an organic solvent. Insome embodiments, the implant contains an organic solvent, or no morethan a trace amount or a residual amount of the organic solvent. Theorganic solvent may be ethanol, dichloromethane, acetone,tetrahydrofuran, or ethyl acetate.

In some embodiments, the drug-containing layer comprises 1, 2, 3, or allof glyceryl behenate, stearic acid, polyanhydroglucuronic acid, and/orpolyethylene oxide. The lipophilic backing layer and/or the hydrophobiccoating may comprise 1, 2, or all of stearic acid, glyceryl behenate,and/or chitosan. In some embodiments, the lipophilic backing layer andthe hydrophobic coating are made of the same or essentially the samecompounds or mixture of compounds. In some embodiments, the lipophilicbacking layer and the hydrophobic coating together form a substantiallyhomogenous hydrophobic layer. In some embodiments, the lipophilicbacking layer and the hydrophobic coating comprise different compounds.The hydrophobic coating may consist of or consist essentially ofglyceryl behenate. In some embodiments, the hydrophobic coatingcomprises glyceryl behenate in combination with 1, 2, 3, or all ofstearic acid, palmitic acid, cholesterol, and/or chitosan. In someembodiments, the drug-containing layer comprises glyceryl behenateand/or stearic acid, in combination with polyanhydroglucuronic acidand/or polyethylene oxide. The drug-containing layer may comprisesglyceryl behenate, stearic acid, and polyethylene oxide. Thedrug-containing layer may further comprises lipase, cholesterol,glyceryl tristearate, and/or poloxamer F-68. In some embodiments, layerc) and/or layer b) contain lipase. The drug-containing layer maycomprise polyethylene oxide or polyanhydroglucoronic acid. Thedrug-containing layer may comprise polyethylene oxide, glycerolbehenate, and/or cholesterol. The drug-containing layer may comprise 1,2, 3, 4, 5, 6, 7, or all of stearic acid, lipase, cholesterol, glycerolbehenate, glyceryl tristearate, poloxamer F-68, and/orpolyanhydroglucuronic acid. The hydrophilic polymer may be apolyethylene oxide, a polysaccharide, a protein, an oxidized cellulosepolymer, polyanhydroglucuronic acid, a poloxomer, chitosan, or providone(PVP). In some embodiments, the implant further comprises lipase. Theimplant is configured for insertion into a resection cavity. In someembodiments, the implant has been cured at temperatures of at leastabout 40° C., 45° C., 50° C., 55° C., 60° C., 65° C., 70° C., 75° C.,80° C., 85° C., 90° C., 95° C., 100° C., or up to 200° C. In someembodiments, the implant has been sterilized by gamma radiation,ethylene oxide, or electron beam radiation. In some embodiments, theimplant or wafer has been processed by compression, hot-melt extrusion,injection molding, dry powder coating, dipping, coating, spraying,hot-melt granulation, casting, an evaporation technology, or anycombination thereof. The implant may comprise: 0.1-50% of the drug,5-95% of the hydrophobic lipid or polymer, and about 3-50% of thehydrophilic polymer or pore forming agent. In some embodiments, theimplant is further defined as a bilayered implant or wafer, or atrilayered implant or wafer. In some embodiments, the implant allows forrelease of the drug over a period of at least 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, or 30 or more days, or at least 1, 2, 3, 4, 5, or 6 weeks, or anyrange derivable therein. The implant may further comprise a surfactant,a carbohydrate, a polyol, a protein, a peptide, and/or an excipient.

Another aspect of the present invention relates to a method of treatinga disease or traumatic injury in a mammalian subject, comprisingadministering into a resection cavity in the subject the implant of thepresent invention or an described above, wherein the drug elutionsurface is positioned proximal to the resection cavity, and, the furtherlayer or layers comprising the lipophilic backing layer and/or thehydrophobic coating are positioned distal and/or lateral to the drugelution surface. The subject may be a mammal such as, e.g., a human. Theresection cavity may be in the brain of the subject. The resectioncavity may be in the spine, lung, neck, knee, back, a joint, bladder, oruterus. The disease may be an inflammatory disease, pain, an infection,or inflammation. In some embodiments, the disease is a cancer. Themethod may further comprise removing part or all of a tumor from thesubject via the resection cavity. In some embodiments, the tumor iscancerous. In some embodiments, the tumor is a brain tumor, aglioblastoma or glioblastoma multiforme, or a high grade intrinsic braintumor. The cancer may be a metastatic cancer. In some embodiments, thesurface of the resection cavity or at least of the part the resectioncavity is filled with a surgical glue or a fibrin glue, e.g., afterwafer implantation. In some embodiments, the resection cavity is filledwith surgical glue e.g., after wafer implantation. The surgical glue maybe, e.g., DuraSeal®, Tiseal® or Eviseal®, or other similar surgicalglue. In some embodiments, part of all of the implant is covered with abiocompatible, biodegradable surgical fabric or Surgicel®.

Some aspects of the present invention may be understood as a method oftreating a cancer in a mammalian subject, comprising administering intoa resection cavity in the subject a pharmaceutically acceptable implantor wafer, wherein the implant or wafer comprises: (i) a firstcomposition comprising an anti-cancer compound, a lipid, and ahydrophilic polymer; and (ii) a second composition comprising ahydrophobic agent; wherein the second composition is located above ordistal to the first composition in the resection cavity.

The method may further comprise administering a third composition intothe resection cavity, wherein the third composition comprises ahydrophilic polymer. The third composition may also enhance thebioadhesiveness of the first composition or the second composition. Insome embodiments, first composition, the second composition, and anythird composition are further defined as pharmaceutical compositions andcomprise an excipient. The first composition may be formulated in theresection cavity between the second composition and the thirdcomposition.

The anti-cancer compound may be a chemotherapy or a chemotherapeuticagent such as temozolomide, paclitaxel, cetuximab, irinotecan,everolimus, carboplatin, or docetaxel. The first composition maycomprise at least a first chemotherapeutic agent and a secondchemotherapeutic agent such as a combination of carboplatin anddocetaxel.

The hydrophobic agent may be a steroid such as cholesterol. In otherembodiments, the hydrophobic agent is a fatty acid such as a saturatedfatty acid. The fatty acid may have 6 to 24 carbon atoms or 12 to 24carbon atoms. A non-limiting example of the fatty acid is stearic acid.In other embodiments, the hydrophobic agent is a glyceride such as amixture of monoglyceride, diglyceride, and triglyceride. The glyceridemixture may predominately contain one or more diglycerides. In someembodiments, the glyceride is a glyceryl behenate. The first compositionmay comprise glyceryl behenate, stearic acid, polyanhydroglucuronicacid, and/or polyethylene oxide. The second composition may comprisepolyethylene oxide, glycerol behenate, and/or cholesterol. The thirdcomposition may comprise stearic acid or glyceryl behenate and/orchitosan.

In some embodiments, the subject is a human. The methods may furthercomprise removing part or all of a tumor from the subject via theresection cavity. In some embodiments, the tumor is cancerous. The tumormay be a brain tumor such as a glioblastoma or glioblastoma multiforme.In some embodiments, the cancer is a metastatic cancer.

The first layer may comprise temozolomide, stearic acid, lipase,cholesterol, glycerol behenate, poloxamer F-68, and/orpolyanhydroglucuronic. The first composition, the second composition,and optionally the third composition may be comprised in a wafer or atablet. The wafer or tablet may be configured for insertion into theresection cavity. In some embodiments, the wafer or tablet furthercomprises an antibiotic or an antimicrobial agent. In some embodiments,the wafer or tablet does not contain dichloromethane (methylenechloride), acetone, tetrahydrofuran, or ethyl acetate. The wafer ortablet may not contain an organic solvent.

The implant or wafer may further comprise an additional therapeuticagent such as an antibiotic, a statin, an anti-fungal agent, ananti-viral agent, an anti-coagulant, a pain medication, an NSAID, or asteroid. The anti-cancer compound may be cisplatin, topotecan,bevacizumab, doxorubicin, everolimus, paclitaxel, irinotecan,carboplatin, D-actinomycin, docetaxel, pitavastatin, methotrexate,temozolomide, epirubicin, cetuximab, a copper chelating agent,carmustine, a synthetic alkyl lysophospholipid, a bioactive sulfatedsaponin, or a statin. The lipid used herein may be glycerol behenate, afatty acid, a cholesterol, a glyceride, a hydrogenated vegetable oil, ortristearin.

The hydrophilic polymer may be polyethylene oxide, chitosan, povidone(PVP), or polyanhydroglucuronic acid. The hydrophilic polymer may be apolyether such as a polyethylene oxide or polypropylene oxide. In someembodiments, the hydrophilic polymer is a polyethylene oxide. Thehydrophilic polymer may be a polysaccharide such as chitosan. In otherembodiments, the hydrophilic polymer comprises a mixture of a polyetherand a polysaccharide such as a mixture of polyethylene oxide andchitosan. The hydrophilic polymer may be a polyethylene oxide, apolysaccharide, a protein, an oxidized cellulose polymer,polyanhydroglucuronic acid, a poloxomer, chitosan, or providone (PVP).The implant or wafer may also further comprise a lipase. In someaspects, the surface of the resection cavity or at least of the part theresection cavity is filled with a surgical glue. In some embodiments,the surgical glue is DuraSeal®, Tiseal® or Eviseal®.

Also contemplated are implant or wafer as described in the abovemethods. The implant or wafer may be pharmacologically acceptable andconfigured for insertion into a resection cavity. The implant or wafermay be cured at temperatures of at least about 40° C., 45° C., 50° C.,55° C., 60° C., 65° C., 70° C., 75° C., 80° C., 85° C., 90° C., 95° C.,100° C., or up to 200° C. The implant or wafer may also be processed bycompression, hot-melt extrusion, injection molding, dry powder coating,hot-melt granulation, casting, evaporation technologies, dipping,spraying, or any combination thereof. In some embodiments, the implantor wafer further comprises an excipient.

In yet another aspect, the present disclosure includes pharmaceuticalbilayered wafer implant composition comprising: a. one or morebiologically active anti-cancer compounds to treat malignant tumorspresent in the brain; b. one or more lipid components; c. one or morewater soluble hydrophilic pore forming polymeric components; d.optionally one or more other inactive pharmaceutical ingredients; e. ahydrophobic second layer, located side-by-side with the drug containinglayer; f. bilayered compositions are then cured at elevatedtemperatures.

The compositions may contain one or more lipid components in the druglayer, including: glycerol behenate, mono, di- and tri-glycerides, longchain fatty acids, cholesterols, and the like. In some embodiments, thecompositions comprise 0.1-50% biologically active compounds, 20-95%lipid component, about 5-50% hydrophilic bioadhesive component and 0-50%suitable additives to enhance processing of the wafer or to control therelease of the active compound from the implant. The pharmaceuticalwafer implant or tablets composition may contain a biologically activecompound in sufficient concentrations to achieve a therapeutic level ofthe compound in a patient over a period of about one week up to aboutsix months. These biologically active compounds may include drugs totreat glioblastoma multiforme. In other embodiments, the biologicallyactive compounds may include drugs to treat a brain tumor such as a highgrade intrinsic brain tumor.

In some embodiments, the biologically active compounds can compoundsalone or in combination to treat and/or cure malignant brain tumors toinclude cisplatin, topotecan, bevacizumab, doxorubicin, everolimus,paclitaxel, irinotecan, carboplatin, D-actinomycin, docetaxel,pitavastatin, methotrexate, temozolomide, epirubicin, cetuximab, copperchelating agents, carmustine, synthetic alkyl lysophospholipids,bioactive sulfated saponins statins and the like. The pharmaceuticalsolid dosage compositions may release the biologically active compoundin the brain over a period of about one week up to six months.Similarly, the compositions may further comprise one or more hydrophilicpolymers comprising polyethylene (oxide), chitosans, poloxymers,polysaccharides, polyols, proteins, polyanhydroglucuronic acid,peptides, providone (PVP) and the like. In some embodiments, thecompositions comprise one or more hydrophilic nonpolymer componentscomprising amino acids. The compositions may also comprise one or moreinert excipients including surfactants, carbohydrates, polyols,proteins, and/or other excipients having no significant effect on the pHof surrounding biological fluid at the site of implantation of the waferin the brain.

In another aspect, the process of preparing bilayered solid dosagecompositions for timed release biologically active anti-cancer compoundsto treat and cure malignant tumors comprising in one layer:

-   -   a. one or more biologically active compounds;    -   b. one or more lipid components;    -   c. one or more hydrophilic polymeric components;    -   d. optionally one or more other pharmaceutical inactive        ingredients; and    -   e. a hydrophobic second layer.

The process may also be performed such that it does not require anorganic solvent. In some embodiments, the process comprises using ahot-melt extrusion, compression, injection molding, evaporation,hot-melt granulation, dry powder coating or the like. In someembodiments, the process comprises preparing a pharmaceuticalcomposition implant by:

-   -   a. dissolve or disperse the anti-cancer compound in molten        liquid carrier;    -   b. disperse or dissolve the hydrophilic polymers in the molten        composition;    -   c. pour the molten mix into molds to form the implant; and    -   d. cool into wafers; or    -   e. alternatively, cool, form granules pass through 60 mesh        screen, compress into wafers or tablets and, cure at elevated        temperature for several hours.

The process may further relate to preparing tablet implant compositionsby compression. The process may further comprise process to preparecompositions that will have no significant influence on the pH of thesurrounding biological fluid following surgical removal of the malignanttumor. The processes relate to the addition to the anti-cancer compoundpresent in the solid pharmaceutical implant compositions to also includeantibiotics, antifungal agents, local anesthetics, NSAIDS, statins,steroids, contraceptives, antivirals, and anti-cancer agents that docross the blood-brain barrier. In some embodiments, the patient is amammal such as a mammal.

In some embodiments, the composition may be sterilized by ethyleneoxide, gamma radiation, or electron beam radiation. The composition mayfurther a lipase. The compositions may also further comprise a poorlywater soluble or water insoluble hydrophobic second layer applied to onesurface of the drug containing tablet or wafer. In some embodiments, thecompositions may be implanted into a patient's brain, immediatelyfollowing the surgical removal of the tumor. The composition may be usedto provide unidirectional delivery of chemotherapeutic agents to thebrain. The compositions may also be applied directly to the wall of thecavity in the brain following surgical removal of the tumor. Thecompositions may also be applied directly to the wall of the resectioncavity in the brain followed by covering with Surgicel® knitted fabric,and/or Duraseal®, Evicel®, or Tisseel® following the surgical removal ofthe tumor. In one embodiment, the resection cavity is filled withsurgical glue. In some embodiments, the compositions also comprise aseparate third layer comprising one or more hydrophilic polymers wherethe final composition comprises a drug containing layer sandwichedbetween the hydrophobic layer and a hydrophilic polymeric layer.

In some aspects, an implant or wafer of the present invention maycomprise temozolomide or other anti-cancer compound(s). The implant orwafer comprising temozolomide or other anti-cancer compounds may beinserted into the resection cavity during the same surgical procedureand/or immediately after the tumor is removed. In some embodiments, anadded advantage of the implant wafers provided in the present inventionis that the patient begins their chemotherapy at the time of surgery.The bioadhesive hydrophilic components in the implant may facilitate thesurgeon applying the device to the wall of the cavity, which can promotedrug diffusion into the brain and not the resection cavity fluid. Theaddition of a second hydrophobic layer to the top surface and/or acoating to desired non-drug eluding sides of the implant can promoteunidirectional drug absorption into the tissue and decrease the releaseof drug into the spinal fluid present in the brain cavity. In contrastto methods of oral administration of temozolomide after a surgery (e.g.,to remove a glioblastoma multiforme tumor) involving a delay between thesurgery and initiation of the temozolomide therapy, the use of animplant or wafer comprising the temozolomide or another anti-cancercompounds may reduce, minimize, or effectively eliminate the delaybetween removal of the tumor and initiation of the additional therapy.In some embodiments, utilizing local delivery of the anti-cancercompounds by using implants in the brain, the systemic dose of thisagent, when delivered orally, may be reduced, which may also decreasethe incidence of known systemic side effects.

In some embodiments, a wafer or tablet of the present invention does notinclude organic solvents such as a polar aprotic or polar proticsolvents. Some non-limiting examples of organic solvents includealcohols, haloalkanes, ketones, esters, and ethers of 12 or less carbonatoms such as ethanol, dichloromethane (or methylene chloride), acetone,tetrahydrofuran, or ethyl acetate. In some embodiments, a wafer ortablet of the present invention may also not include any of the waterinsoluble polymers that are described in the U.S. Pat. No. 8,821,913.

“Unidirectional” as used herein refers to the diffusion of a therapeuticcompound (e.g., anti-cancer compound, chemotherapeutic compound, etc.)out of an implant or wafer of the present invention. A “backing” layerand/or hydrophilic coating containing a hydrophobic material may reduce,minimize, or prevent the therapeutic compound from travelling through aresection cavity towards the exterior surface of a subject (e.g.,towards the skull or scalp of a human patient).

In some aspects, the implants or wafers use a hydrophobic agent that islayered distal to or onto the surface of the drug containing layer topromote unidirectional absorption through the wall of the cavity in thebrain, following tumor removal. The presence of an optional thirdhydrophilic layer added to the implant may promote adhesion of theimplant directly to the brain along the sides of the resection cavity.The drug containing layer would be “sandwiched” between the hydrophobicand adhesive layer. To further promote the unidirectional flow of thechemotherapeutic agent through the wall of the brain cavity, theimplants of the present invention may preferably be held in place with acovering of Surgicel®, a surgical knitted fabric, or a surgical gluesuch as DuraSeal®, Tiseal® or Eviseal®. The surgical glue applied to thehydrophobic layer of the implant, may harden within seconds and may notonly maintain adherence of the implant to the wall of the brain cavity,but may also help prevent drug release from the sides of the implantinto the brain cavity, thereby promoting the unidirectional absorptionof drug from the implant into the local environment of the brain.

The hydrophilic polymers present in the drug containing layer of theimplant may influence both the erosion and permeability of the implant.The curing of the wafer at elevated temperature can increase theadhesion amongst layers in the implant. Preferred hydrophilic polymersinclude polyethylene oxide, chitosan, povidone (PVP) andpolyanhydroglucuronic acid. The lipids may be slowly broken down byenzymes in the lipase family, which are normally found throughout thehuman body. Additional added low doses of lipase in the dosage form mayalso control the release rate of the active compound from the dosageform. Lipase levels in the blood serum have been reported to increaseafter surgery but then decline sharply, particularly in the brain. Insome embodiments, about 1.5-4%, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5% orany range derivable therein of polyethylene oxide may be particularlyuseful in implants or wafers of the present invention.

As used herein the specification, “a” or “an” may mean one or more. Asused herein in the claim(s), when used in conjunction with the word“comprising”, the words “a” or “an” may mean one or more than one.

The use of the term “or” in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive, although the disclosure supports a definitionthat refers to only alternatives and “and/or.” As used herein “another”may mean at least a second or more.

Throughout this application, the term “about” is used to indicate that avalue includes the inherent variation of error for the device, themethod being employed to determine the value, or the variation thatexists among the study subjects.

Other objects, features and advantages of the present invention willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein.

FIG. 1: Release from single layer wafers. Each of the single layerwafers were tested with different PolyOx 303 (solid line and soliddiamond, 0% PolyOx 303; solid line and open square, 1.5% PolyOx 303;dashed line and open diamond, 3% PolyOx 303; dashed lines and soliddiamond, 4% PolyOx 303; and solid line and solid square, 5% PolyOx 303)

FIG. 2: Release from coated bilayer wafers with different grades of PEOand different levels (0-3%) of PEO. (solid line and solid diamond, NoPEO; dashed line and solid cross, 1.5% PolyOx N10; dashed line and opendiamond, 1.5% PolyOx N12K, dashed line and solid diamond, 1.5% PolyOx303; solid line and solid diamond, 3% PolyOx N10; solid line and opensquare, 3% PolyOx N12K; and solid line and solid square, 3% PolyOx 303).Release of acetaminophen (APAP) from coated bi-layer (bio-adhesive layerand drug layer) wafer was measured. The drug layer composition included5% APAP, the above noted percent of PEO of various grades, and glycerolbehenate q.s. to 100%, a total of 200 mg including a bio-adhesive layerof 50 mg PEO 303. These compositions were used to investigate thepercent of PEO and grade of PEO on drug release from coated bi-layerwafer. Without the hydrophobic backing layer, portion of drug layermelted away during dip-coating process. As a result, only 75% drug wasrecovered at the end of the drug release testing. As a result of thesedata, it may be concluded that the higher the PEO molar mass, the fasterthe drug release is and the higher the percent of PEO, the faster thedrug release is.

FIG. 3: Release from coated bilayers with different grades and levels(4-5%) of PEO. (dashed line and solid cross, 4% PolyOx N10; solid lineand open square, 4% PolyOx N12K, solid line and solid square, 4% PolyOx303; dashed line and open diamond, 5% PolyOx N10; dashed line and soliddiamond, 5% PolyOx N12K; and solid line and solid diamond, 5% PolyOx303).

FIG. 4: Release from single layered, bi-layer, and tri-layered wafers.Release of acetaminophen (APAP) from single (drug layer), bi-layer (druglayer+hydrophobic layer) and tri-layer (bio-adhesive layer, drug layer,hydrophobic layer and coating) wafer. The composition of the waferincludes: (1) Drug layer composition: 5% APAP, 3% PEO 303, and 92%glycerol behenate, (2) Hydrophobic layer: 100 mg glycerol behenate, and(3) Bioadhesive layer: 50 mg PolyOx 303. The effect of the coating andbioadehsive layer on APAP release was analyzed. As can be seen in thefigure, the coating slowed down drug release by reducing the totalsurface area available for drug release. Without wishing to be bound byany theory, the presence of bio-adhesive layer accelerated drug releasemay be based upon increased facilitation the hydration of drug layer.

FIG. 5: Effect of curing at 73° C. for 10 minutes on the release ofacetaminophen (APAP) from tri-layer (bio-adhesive layer, drug layer,hydrophobic layer and coating) wafer. The drug composition includes: (1)Drug layer composition: 5% APAP, 3% PEO 303, and 92% glycerol behenate,a total of 200 mg; (2) Hydrophobic layer composition: 100 mg glycerolbehenate; and (3) Bio-adhesive layer composition: 50 mg PolyOx 303. Theeffects of curing on the APAP release showed that the curing and uncuredsamples had similar release profiles.

FIG. 6: DSC Thermogram of APAP, compritol, their mixture prepared byphysical blending, and their mixture prepared using melt granulation.

FIG. 7: An embodiment of a multi-layered wafer.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

In some aspects, wafers or implants are provided that may be used todeliver a therapeutic agent to a resection cavity in the tissue of asubject, e.g., after surgical removal of tissue. For example, the waferor implant may be used to deliver a chemotherapeutic agent to the brainof a subject after removal of a tumor from the brain of the subject. Insome embodiments, the implant or wafer comprises multiple layers thatmay promote release of the therapeutic agent into the tissue, which mayresult in an improved therapeutic benefit.

In some aspects, a one or more anticancer compounds may be included in awafer or implant of the present invention (e.g., for the treatmentglioblastoma multiforme). In some embodiments, the anticancer compoundincluded in the wafer or implant is a compound that does not cross theblood-brain barrier in sufficient amounts to exert a therapeuticresponse when delivered by oral or parenteral routes. Thus, in theseembodiments, the wafer or implant can provide a particularly usefulopportunity to deliver a therapeutic compound to or near to the site ofsurgery in the brain, where it would be otherwise difficult to deliverthat compound due to the particular pharmacokinetics, etc. of theanti-cancer compound. Other adjunct non-therapeutic compounds may beincluded in the formulations, including absorption enhancing substances,antioxidants and other functional excipients. In some embodiments,little or no acidic byproducts are formed from the slow erosion of thesolid dosage forms since the lipids and hydrophilic polymers can have aninsignificant, minimal, or no effect on the pH of the surroundingbiological fluid at the site of implantation. Thus, in accordance withone aspect, the present invention includes pharmaceutical implantcompositions as anti-cancer drug delivery systems comprising asingredients:

-   -   (a) anti-cancer compound(s);    -   (b) lipid compound(s);    -   (c) hydrophilic polymeric agent(s);    -   (d) optional pharmaceutical additives or excipients including        enzymes or other active pharmaceutical ingredients;    -   (e) a hydrophobic top layer and/or coating; and an optional        third layer comprising hydrophilic polymer(s).        The anti-cancer compounds in (a) (above) may include: cisplatin,        topotecan, bevacizumab, doxorubicin, everolimus, paclitaxel,        irinotecan, carboplatin, D-actinomycin, docetaxel, pitavastatin,        methotrexate, temozolomide, epirubicin, cetuximab, copper        chelating agents, carmustine, synthetic alkyl lysophospholipids,        bioactive sulfated saponins, statins and the like. The nonionic        lipid compounds in (b) (above) may include: glycerol behenate,        fatty acid, cholesterol, glycerides, hydrogenated vegetable        oils, tristearin, stearic acid, and the like. The water soluble        hydrophilic polymeric pore forming agents included in the drug        containing layer, (c), above) as well as polymers comprising the        optional third layer in the implants, (f), above), include:        polyethylene oxides, polysaccharides, proteins, oxidized        cellulose polymers, polyanhydroglucuronic acid, poloxomers,        chitosan, providone (PVP) and the like. Temozolomide is an        alkalating agent that may be used, e.g., to treat malignant        primary brain tumors. Temozolomide is generally 100%        bioavailable in the systemic bloodstream of the patient when        taken orally and is able to cross the blood-brain barrier,        however the concentrations in the central nervous system have        been reported to only be approximately 30% of plasma        concentrations. Temozolomide has lipophilic properties and is a        low molecular weight molecule. This compound typically must be        present in the CNS in order for it to be converted to the active        metabolite.

In some embodiments, a secondary therapeutic agent is included in theimplant or wafer in addition to the anti-cancer agent. The implant wafercompositions may comprise an optional secondary therapeutic agentsincluding, e.g., one or more antibiotics, statins, anti-fungals,anti-virals, pain medications, contraceptives, NSAIDS and steroids, toachieve simultaneous administration of the agents to a cancer patient.Such agents may be included with the anti-cancer compound in the wafercompositions of the present compositions or may be administered to thepatient in a separate wafer.

The present invention also provides, in some aspects, methods ofpreparation of the wafers. For example, the pharmaceutical wafercompositions of the present invention may be processed by compression,hot-melt extrusion, injection molding, dry powder coating, hot-meltgranulation, casting, evaporation technologies, dipping, spraying, orcombinations of these methods. Elevated temperature curing is utilizedto promote adhesion of the layers in the wafer.

In some aspects, implant wafers and methods provided herein may be usedto maintain therapeutic concentrations of the drug at the site ofimplantation following surgical removal of the tumor, e.g., from about1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks, or 1, 2, 3, 4, 5, 6 months, or anyrange derivable therein. The particular rate of diffusion or release ofthe active agent, therapeutic agent, or anticancer agent may be variedor affected based the composition of the drug delivery system (e.g.,particular polymers included in the implant or capsule, ratio ofhydrophilic and hydrophobic polymers included, etc.) and the dose of theactive moiety being delivered.

A. Hydrophilic Compound or Polymer

A variety of hydrophilic compounds or polymers may be included in animplant or wafer of the present invention. For example, in someembodiments, the hydrophilic compound is polyanhydroglucuronic acid.This material is currently used in surgery as a hemostatic agent toreduce blood clots and to promote wound healing. It is also an effectiveantibacterial agent. Polyanhydroglucuronic acid is an oxidized cellulosepolymer with a basic unit of polyanhydroglucuronic acid. Relatedmaterials are described in U.S. Pat. No. 3,364,200.Polyanhydroglucuronic acid is the base material in the Surgicel® knittedfabric product that has has been used in surgery, includingneurosurgery.

In some aspects of the present disclosure, the composition comprises ahydrophilic polymer. Hydrophilic polymers may contain polar or chargedgroups such that the polymer is soluble in water or aqueous mixtures. Inparticular, the hydrophilic polymers contain one or more groups, whichcan act as a hydrogen bond donor or acceptor or a charged group such asa carboxylic acid group or an amine group. Some non-limiting examples ofhydrophilic polymers include: polyacrylamide, polyimines, polyacrylicacid, polyethylene oxide, polypropylene oxide, polyvinyl alcohol,polyvinylpyrrolidone, polyether, polymers of maleic anhydride,polyelectrolytes such as polystyrenesulfonates, or other water solublegroups such as cucurbit[n]uril.

In some embodiments, the hydrophilic polymer is a polyether. Forexamples, a polyether polymers that may be used in various embodimentsinclude polyethylene oxide (also known as polyethylene glycol, PEG, orPEO) and polypropylene oxide (PPO). PEO is the polymeric form ofethylene glycol, while PPO is the polymeric form of propylene glycol.The formula of PEO and PPO, respectively, are shown below:

H(OCH₂CH₂)_(n)OH  (I)

H(OCH₂CH₂CH₂)_(n)OH  (II)

wherein the repeating unit, n, is an integer. In some aspects, thenomenclature used to describe PEO includes the average molecular weightof the polymer (e.g. PEO-400; PEO-500, PEO-600, etc.) In someembodiments, the molecular weight of PEO ranges from about 100,000 toabout 7,000,000 daltons (e.g., PEO 303), more preferably from about1,000,000 to about 7,000,000 daltons. In some embodiments, the molecularweight of the PEO is about 1e5, 2.5e5, 5e5, 1e6, 2e6, 3e6, 4e6, 5e6,6e6, 7e6, 8e6 daltons, or any range derivable therein. As would beobvious to a person of skill in the art, the average molecular weightdoes not mean that any particular PEO or PPO molecule within thecomposition has the noted molecular weight but rather that thecomposition as a whole has the average molecular weight corresponding tothat value. In some embodiments, the PEO or PPO molecule can have one orboth of the terminal hydrogen atoms can be replaced with another groupincluding but not limited to an alkyl group (e.g. a methyl group or anethyl group).

In other embodiments, the composition comprises a hydrophilic polymerwhich is a natural biopolymer. The hydrophilic polymer may be a naturalbiopolymer such as, e.g., a polysaccharide. Polysaccharides areoligomers of sugars such as, e.g., glucose, fructose, galactose, xylose,and arabinose. Some non-limiting examples of polysaccharides which maybe used include glycogen, amylose, amylopectin, arabinoxylan, cellulose,chitin or chitosan, or pectin. In some embodiments, the polysaccharideis chitin or chitosan.

In some embodiments, the wafer or implant may comprise one or morepharmaceutical additives or excipients that aid processing and canregulate the release of the active drug substance from the wafer. Suchadditives or excipients include, e.g., biocompatible surfactants,lipase, lecithin, polyols, proteins, enzymes, peptides and the like, andother suitable agents familiar to a person skilled in the art ofpreparing solid pharmaceutical dosage forms. The presence of lipase inthe solid dosage form, may aid in the metabolism and elimination of fatsand lipids at the implant site. The presence of absorption enhancingagents such as sodium lauryl sulfate and the polysorbates may also beincluded in the drug containing layer of the implant.

B. Hydrophobic Compounds or Agents

In some embodiments, the composition of one or more of the layerscontains a hydrophobic compound or hydrophobic agent. These hydrophobiccompounds may include steroids, fatty acids, and/or glycerides. When alipid is used in the wafer or capsule, it is anticipated that the lipidmay be used in conjunction with or substituted for one or more thehydrophobic compounds described herein (e.g. a fatty acid or glyceridemay be included instead of the lipid).

Steroids are compounds which contain a four ring fused structure asshown below:

also known as hexadecahydro-1H-cyclopenta[a]phenanthrene. The steroidsdescribed herein may have a hydroxy or oxo substituted on carbon atom 3and are commonly substituted with an alkyl group at one or more ofcarbon atoms 10, 13 and 17. In some embodiments, the hydroxysubstitution at position 3 of the steroid is in the β orientation. Insome embodiments, the alkyl groups are at carbon atom 17. Withoutwishing to be bound by any theory, it is believed that steroids with anysubstituents on the ring, other orientations, salt forms and other knownvariations of the basic ring may be used in the compositions describedherein. Some non-limiting examples of steroids include cholesterol,androstenolone, androsterone, brassicasterol, calciferol, campesterol,cholestanol, cholestenone, coprostene, cortisone, demosterol, diosgenin,dihydrocalciferol, ergosterol, epicholestanol, estrone, estradiol,fucosterol, hecogenin, hexahydrolumisterol, lanosterol, lumisterol,pregnenolone, progesterone, oestrone, sarsasapogenin, sitosterol,smilagenin, spinastenol, stigmasterol, stigmastanol, testosterone,tigogenin and tomatidine. In some embodiments, the steroids used hereinis cholesterol.

In other embodiments, the compositions of the present disclosure mayinclude fatty acids and/or glycerides. Fatty acids are long chain alkylgroups with a carboxylic acid at one end. In some embodiments, alkylgroup of the fatty acid has from 6 to 24 carbon atoms. These fatty acidswhich do not contain any double bonds are saturated fatty acids. Fattyacids may also contain one or more double bonds in the alkyl group.Fatty acids containing one or more double bonds are unsaturated fattyacids. If double bonds are present in the fatty acid, these double bondsmay be in the cis orientation. The alkyl group may comprise 1, 2, or 3double bonds. Some non-limiting examples of fatty acids include: butyricacid, caproic acid, caprylic acid, capric acid, lauric acid, myristicacid, palmitic acid, margaric acid, stearic acid, arachidic acid,behenic acid, lignoceric acid, palmitoleic acid, oleic acid, elaidicacid, vaccenic acid, gondoic acid, erucic acid, mead acid, linoleicacid, α-linoleic acid, stearidonic acid, γ-linoleic acid, arachidonicacid, eicosapentaenoic acid, docosahexaenoic acid, or nervonic acid.

In other embodiments, the compositions of the present disclosure mayinclude glycerides. Glycerides comprise esters of the glycerol and one,two, or three fatty acids of the described herein. As would beunderstood by a person of skill in the art, a monoglyceride is aglycerol esterified to one fatty acid, a diglyceride is a glycerolesterified to two fatty acids, and a triglyceride is a glycerideesterified to three fatty acids. It is also contemplated that theglycerides may be substituted with one or more other groups such as anamino acid, choline, a phosphate group, an alkylamino, or anycombination of theses groups.

The term “unit dose” or “dosage” refers to physically discrete unitssuitable for use in a subject, each unit containing a predeterminedquantity of the therapeutic composition calculated to produce thedesired responses discussed above in association with itsadministration, i.e., the appropriate route and treatment regimen. Thequantity to be administered, both according to number of treatments andunit dose, depends on the effect desired. The actual dosage amount of acomposition of the present embodiments administered to a patient orsubject can be determined by physical and physiological factors, such asbody weight, the age, health, and sex of the subject, the type ofdisease being treated, the extent of disease penetration, previous orconcurrent therapeutic interventions, idiopathy of the patient, theroute of administration, and the potency, stability, and toxicity of theparticular therapeutic substance. In other non-limiting examples, a dosemay also comprise from about 1 microgram/kg/body weight, about 5microgram/kg/body weight, about 10 microgram/kg/body weight, about 50microgram/kg/body weight, about 100 microgram/kg/body weight, about 200microgram/kg/body weight, about 350 microgram/kg/body weight, about 500microgram/kg/body weight, about 1 milligram/kg/body weight, about 5milligram/kg/body weight, about 10 milligram/kg/body weight, about 50milligram/kg/body weight, about 100 milligram/kg/body weight, about 200milligram/kg/body weight, about 350 milligram/kg/body weight, about 500milligram/kg/body weight, to about 1000 milligram/kg/body weight or moreper administration, and any range derivable therein. In non-limitingexamples of a derivable range from the numbers listed herein, a range ofabout 5 milligram/kg/body weight to about 100 milligram/kg/body weight,about 5 microgram/kg/body weight to about 500 milligram/kg/body weight,etc., can be administered, based on the numbers described above. Thepractitioner responsible for administration will, in any event,determine the concentration of active ingredient(s) in a composition andappropriate dose(s) for the individual subject. In certain embodiments,the compositions and methods of the present embodiments involveadministration of an implant in a resection cavity as described hereinin combination with a second or additional therapy. Such therapy can beapplied in the treatment of any disease that is responsive to CDC. Forexample, the disease may be cancer.

C. Implant Characteristics and Production

In some embodiments, the multilayered wafer implants of the presentinvention may weigh between about 50 mg and 800 mg, more preferablyabout 100-400 mg. The diameter of the wafer may vary from about 0.25-3centimeters, with one to two centimeters being more preferred. Thethickness of these wafers may vary from about 0.5-5.0 mm, with 0.75 mmto 2.0 mm being more preferred. The drug content may depend upon theprocessing and physical and chemical properties of the drug, polymersand lipids as well as the compressibility and thermal stability. Thepotency of the wafers may vary from about 0.1% to 60%, with about 5-30%being more preferred. The shape of the wafer implants can be prepared ina variety of configurations such as, e.g., circular, square, rectangularor oblong, and the implants can be cut or split in half or into smallerparticles as desired by the neurosurgeon at the time of implantation. Inaddition, the wafers may have surfaces that are concave or convex. Thewafers can be sterilized, e.g., by the use of gamma radiation, ethyleneoxide, or electron beam radiation. Bilayered and trilayered wafers canbe prepared by compression on a tablet press or a Carver press. A meltgranulated powder blend of the lipid and drug components are physicallyblended with hydrophilic polymer for the drug containing layer and maybe first added to the die, followed by the wax or lipid used as the toplayer in the implant. The compressed wafer may then be heated atelevated temperatures of about 65° C. for 2-4 hours or 73° C. for 10minutes or a temperature between the two. The curing temperature shouldbe a few degrees below the melting point of the hydrophobic retardant,to adhere the hydrophobic layer to the drug containing layer.

Alternately, in some embodiments, for the three layered wafer, the firstcomponent that is present in the die is the hydrophilic polymer followedby the powder blend containing the chemotherapeutic agent containinglayer and finally the hydrophobic powder is added. The compressed wafermay then be heat treated as described above.

Additionally, a hydrophobic coating may be applied through a dipping,spraying, or similar technique to further promote unidirectionality andslow drug release. In some embodiments, the coating covers the wafers onall or substantially all sides where drug release is non-desirable. Insome embodiments, the bioadhesive layer is left mostly or completelyuncoated, and the backing and sides are covered with the hydrophobiccoating.

In some embodiments, the hydrophilic polymeric layer be prepared by hotmelt extrusion. A molten dispersion comprising the lipid, hydrophilicpolymer, chemotherapeutic agent and other optional ingredients may thenapplied to the film and allowed to cool. The final layer of molten lipidor wax may then be applied. The resulting film may then be cut intowafers of desired dimensions. The resulting wafers may then be cured atelevated temperature for up to about 4 hours. For example, the resultingwafer is cured for a time period from about 5 minutes to about 4 hours,or from about 2 hours to about 4 hours.

D. Indications

In some preferred embodiments, an implant is applied to a resectioncavity (e.g., in the brain) after surgical removal of a canceroustissue. In other embodiments, the implant may be applied to a resectioncavity (e.g., in the brain or other portion of the body) after removalof a non-cancerous tissue.

A variety of cancers may be treated using an implant of the presentinvention. A tumor that is removed from the brain of a subject (e.g., ahuman patient) may be cancerous, precancerous, or benign. In someembodiments, the tumor is cancerous. The tumor in the brain may haveoriginated in the brain of the subject (e.g., a brain cancer) or thetumor may have originated in a different part of the body (e.g., ametastatic cancer that has originated in some other part of the body buthas traveled to the brain). Tumors for which the present treatmentmethods are useful include any malignant cell type, such as those foundin a solid tumor or a hematological tumor. Exemplary solid tumors caninclude, but are not limited to, a tumor of an organ selected from thegroup consisting of pancreas, colon, cecum, stomach, brain, head, neck,ovary, kidney, larynx, sarcoma, lung, bladder, melanoma, prostate, andbreast. Exemplary hematological tumors include tumors of the bonemarrow, T or B cell malignancies, leukemias, lymphomas, blastomas,myelomas, and the like. Further examples of cancers that may be treatedusing the methods provided herein include, but are not limited to,carcinoma, lymphoma, blastoma, sarcoma, leukemia, squamous cell cancer,lung cancer (including small-cell lung cancer, non-small cell lungcancer, adenocarcinoma of the lung, and squamous carcinoma of the lung),cancer of the peritoneum, hepatocellular cancer, gastric or stomachcancer (including gastrointestinal cancer and gastrointestinal stromalcancer), pancreatic cancer, glioblastoma, cervical cancer, ovariancancer, liver cancer, bladder cancer, breast cancer, colon cancer,colorectal cancer, endometrial or uterine carcinoma, salivary glandcarcinoma, kidney or renal cancer, prostate cancer, vulval cancer,thyroid cancer, various types of head and neck cancer, melanoma,superficial spreading melanoma, lentigo malignant melanoma, acrallentiginous melanomas, nodular melanomas, as well as B-cell lymphoma(including low grade/follicular non-Hodgkin's lymphoma (NHL); smalllymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediategrade diffuse NHL; high grade immunoblastic NHL; high gradelymphoblastic NHL; high grade small non-cleaved cell NHL; bulky diseaseNHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom'smacroglobulinemia), chronic lymphocytic leukemia (CLL), acutelymphoblastic leukemia (ALL), Hairy cell leukemia, multiple myeloma,acute myeloid leukemia (AML) and chronic myeloblastic leukemia.

The cancer may specifically be of the following histological type,though it is not limited to these: neoplasm, malignant; carcinoma;carcinoma, undifferentiated; giant and spindle cell carcinoma; smallcell carcinoma; papillary carcinoma; squamous cell carcinoma;lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma;transitional cell carcinoma; papillary transitional cell carcinoma;adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma;hepatocellular carcinoma; combined hepatocellular carcinoma andcholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma;adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposiscoli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolaradenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma;acidophil carcinoma; oxyphilic adenocarcinoma; basophil carcinoma; clearcell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma;papillary and follicular adenocarcinoma; nonencapsulating sclerosingcarcinoma; adrenal cortical carcinoma; endometroid carcinoma; skinappendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma;ceruminous adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma;papillary cystadenocarcinoma; papillary serous cystadenocarcinoma;mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cellcarcinoma; infiltrating duct carcinoma; medullary carcinoma; lobularcarcinoma; inflammatory carcinoma; paget's disease, mammary; acinar cellcarcinoma; adenosquamous carcinoma; adenocarcinoma w/squamousmetaplasia; thymoma, malignant; ovarian stromal tumor, malignant;thecoma, malignant; granulosa cell tumor, malignant; androblastoma,malignant; sertoli cell carcinoma; leydig cell tumor, malignant; lipidcell tumor, malignant; paraganglioma, malignant; extra-mammaryparaganglioma, malignant; pheochromocytoma; glomangiosarcoma; malignantmelanoma; amelanotic melanoma; superficial spreading melanoma; malignantmelanoma in giant pigmented nevus; epithelioid cell melanoma; bluenevus, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma,malignant; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma;embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma;mixed tumor, malignant; mullerian mixed tumor; nephroblastoma;hepatoblastoma; carcinosarcoma; mesenchymoma, malignant; brenner tumor,malignant; phyllodes tumor, malignant; synovial sarcoma; mesothelioma,malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant;struma ovarii, malignant; choriocarcinoma; mesonephroma, malignant;hemangiosarcoma; hemangioendothelioma, malignant; kaposi's sarcoma;hemangiopericytoma, malignant; lymphangiosarcoma; osteosarcoma;juxtacortical osteosarcoma; chondrosarcoma; chondroblastoma, malignant;mesenchymal chondrosarcoma; giant cell tumor of bone; ewing's sarcoma;odontogenic tumor, malignant; ameloblastic odontosarcoma; ameloblastoma,malignant; ameloblastic fibrosarcoma; pinealoma, malignant; chordoma;glioma, malignant; ependymoma; astrocytoma; protoplasmic astrocytoma;fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma;oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma;ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactoryneurogenic tumor; meningioma, malignant; neurofibrosarcoma;neurilemmoma, malignant; granular cell tumor, malignant; malignantlymphoma; hodgkin's disease; hodgkin's; paragranuloma; malignantlymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse;malignant lymphoma, follicular; mycosis fungoides; other specifiednon-hodgkin's lymphomas; malignant histiocytosis; multiple myeloma; mastcell sarcoma; immunoproliferative small intestinal disease; leukemia;lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcomacell leukemia; myeloid leukemia; basophilic leukemia; eosinophilicleukemia; monocytic leukemia; mast cell leukemia; megakaryoblasticleukemia; myeloid sarcoma; and hairy cell leukemia.

The methods and compositions, including combination therapies, mayenhance the therapeutic or protective effect, and/or increase thetherapeutic effect of another anti-cancer or anti-hyperproliferativetherapy. Therapeutic and prophylactic methods and compositions can beprovided in a combined amount effective to achieve the desired effect,such as the killing of a cancer cell and/or the inhibition of cellularhyper proliferation. This process may involve administering apolypeptide or antibody and a second therapy. The second therapy may ormay not have a direct cytotoxic effect. For example, the second therapymay be an agent that upregulates the immune system without having adirect cytotoxic effect. A tissue, tumor, or cell can be exposed to oneor more compositions or pharmacological formulation(s) comprising one ormore of the agents (e.g., a polypeptide or an anti-cancer agent), or byexposing the tissue, tumor, and/or cell with two or more distinctcompositions or formulations, wherein one composition provides 1) apolypeptide or antibody, 2) an anti-cancer agent, or 3) both apolypeptide or antibody and an anti-cancer agent. Also, it iscontemplated that such a combination therapy can be used in conjunctionwith chemotherapy, radiotherapy, surgical therapy, or immunotherapy.

The terms “contacted” and “exposed,” when applied to a cell, are usedherein to describe the process by which a therapeutic polypeptide orantibody and a chemotherapeutic or radio therapeutic agent are deliveredto a target cell or are placed in direct juxtaposition with the targetcell. To achieve cell killing, for example, both agents are delivered toa cell in a combined amount effective to kill the cell or prevent itfrom dividing.

E. Combination Therapies

An implant in a resection cavity as described herein may be administeredbefore, during, after, or in various combinations relative to ananti-cancer treatment. The administrations may be in intervals rangingfrom concurrently to minutes to days to weeks. In embodiments where animplant in a resection cavity as described herein is provided to apatient separately from an anti-cancer agent, one would generally ensurethat a significant period of time did not expire between the time ofeach delivery, such that the two compounds would still be able to exertan advantageously combined effect on the patient. In such instances, itis contemplated that one may provide a patient with the polypeptide andthe anti-cancer therapy within about 12 to 24 or 72 h of each other and,more particularly, within about 6-12 h of each other. In some situationsit may be desirable to extend the time period for treatmentsignificantly where several days (2, 3, 4, 5, 6, or 7) to several weeks(1, 2, 3, 4, 5, 6, 7, or 8) lapse between respective administrations.

In certain embodiments, a course of treatment will last 1-90 days ormore (this range includes intervening days). It is contemplated that oneagent may be given on any day of day 1 to day 90 (this range includesintervening days) or any combination thereof, and another agent is givenon any day of day 1 to day 90 (this range includes intervening days) orany combination thereof. Within a single day (24-hour period), thepatient may be given one or multiple administrations of the agent(s).Moreover, after a course of treatment, it is contemplated that there isa period of time at which no anti-cancer treatment is administered. Thistime period may last 1-7 days, and/or 1-5 weeks, and/or 1-12 months ormore (this such range includes intervening days), depending on thecondition of the patient, such as their prognosis, strength, health,etc. It is expected that the treatment cycles would be repeated asnecessary.

Various combinations may be employed. For the example below apolypeptide or antibody is “A” and an anti-cancer therapy is “B”:

A/B/AB/A/BB/B/AA/A/BA/B/BB/A/AA/B/B/BB/A/B/B BBB/A B/B/A/B A/A/B/BA/B/A/BA/B/B/AB/B/A/A B/A/B/A B/A/A/B A/A/A/BB/A/A/AA/B/A/AA/A/B/A

Administration of any implant in a resection cavity as described hereinor therapy of the present embodiments to a patient will follow generalprotocols for the administration of such compounds, taking into accountthe toxicity, if any, of the agents. Therefore, in some embodimentsthere is a step of monitoring toxicity that is attributable tocombination therapy.

A. Chemotherapy

A wide variety of chemotherapeutic agents may be used in accordance withthe present embodiments. For example, a chemotherapeutic may becomprised in an implant (e.g., a drug wafer implant comprising a lipidand a hydrophobic polymer). The drug may be a chemotherapeutic. It isenvisioned that virtually any chemotherapy or chemotherapeutic agentknown may be included in an implant (e.g., a drug wafer implant) or usedin various embodiments of the present invention. In some embodiments,the chemotherapeutic agent may be included in a drug wafer implant toachieve a local concentration in the brain (e.g., near the injectionsite) that is significantly higher than the systemic concentration thatone would typically be able to achieve by systemic administration of thechemotherapeutic agent. Alternately, an implant in a resection cavity asdescribed herein may be used in combination with administration or achemotherapy agent or other therapy as described herein.

The term “chemotherapy” refers to the use of drugs to treat cancer. A“chemotherapeutic agent” is used to connote a compound or compositionthat is administered in the treatment of cancer. These agents or drugsare categorized by their mode of activity within a cell, for example,whether and at what stage they affect the cell cycle. Alternatively, anagent may be characterized based on its ability to directly cross-linkDNA, to intercalate into DNA, or to induce chromosomal and mitoticaberrations by affecting nucleic acid synthesis.

Examples of chemotherapeutic agents include alkylating agents, such asthiotepa and cyclosphosphamide; alkyl sulfonates, such as busulfan,improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone,meturedopa, and uredopa; ethylenimines and methylamelamines, includingaltretamine, triethylenemelamine, trietylenephosphoramide,triethiylenethiophosphoramide, and trimethylolomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (including thesynthetic analogue topotecan); bryostatin; callystatin; CC-1065(including its adozelesin, carzelesin and bizelesin syntheticanalogues); cryptophycins (particularly cryptophycin 1 and cryptophycin8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin;spongistatin; nitrogen mustards, such as chlorambucil, chlornaphazine,cholophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, and uracil mustard;nitrosureas, such as carmustine, chlorozotocin, fotemustine, lomustine,nimustine, and ranimnustine; antibiotics, such as the enediyneantibiotics (e.g., calicheamicin, especially calicheamicin gammall andcalicheamicin omegall); dynemicin, including dynemicin A;bisphosphonates, such as clodronate; an esperamicin; as well asneocarzinostatin chromophore and related chromoprotein enediyneantiobiotic chromophores, aclacinomysins, actinomycin, authrarnycin,azaserine, bleomycins, cactinomycin, carabicin, carminomycin,carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, doxorubicin (includingmorpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins, such as mitomycin C, mycophenolicacid, nogalarnycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, and zorubicin; anti-metabolites, such asmethotrexate and 5-fluorouracil (5-FU); folic acid analogues, such asdenopterin, pteropterin, and trimetrexate; purine analogs, such asfludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidineanalogs, such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine;androgens, such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, and testolactone; anti-adrenals, such as mitotane andtrilostane; folic acid replenisher, such as frolinic acid; aceglatone;aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids, suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSKpolysaccharidecomplex; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid;triaziquone; 2,2′,2″-trichlorotriethylamine; trichothecenes (especiallyT-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine;dacarb azine; mannomustine; mitobronitol; mitolactol; pipobroman;gacytosine; arabinoside (“Ara-C”); cyclophosphamide; taxoids, e.g.,paclitaxel and docetaxel gemcitabine; 6-thioguanine; mercaptopurine;platinum coordination complexes, such as cisplatin, oxaliplatin, andcarboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide;mitoxantrone; vincristine; vinorelbine; novantrone; teniposide;edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan(e.g., CPT-11); topoisomerase inhibitor RFS 2000;difluorometlhylornithine (DMFO); retinoids, such as retinoic acid;capecitabine; carboplatin, procarbazine, plicomycin, gemcitabien,navelbine, farnesyl-protein transferase inhibitors, transplatinum, andpharmaceutically acceptable salts, acids, or derivatives of any of theabove.

B. Radiotherapy

Other factors that cause DNA damage and have been used extensivelyinclude what are commonly known as γ-rays, X-rays, and/or the directeddelivery of radioisotopes to tumor cells. Other forms of DNA damagingfactors are also contemplated, such as microwaves, proton beamirradiation (U.S. Pat. Nos. 5,760,395 and 4,870,287), andUV-irradiation. It is most likely that all of these factors affect abroad range of damage on DNA, on the precursors of DNA, on thereplication and repair of DNA, and on the assembly and maintenance ofchromosomes. Dosage ranges for X-rays range from daily doses of 50 to200 roentgens for prolonged periods of time (3 to 4 wk), to single dosesof 2000 to 6000 roentgens. Dosage ranges for radioisotopes vary widely,and depend on the half-life of the isotope, the strength and type ofradiation emitted, and the uptake by the neoplastic cells.

C. Immunotherapy

The skilled artisan will understand that immunotherapies may be used incombination or in conjunction with methods of the embodiments. In thecontext of cancer treatment, immunotherapeutics, generally, rely on theuse of immune effector cells and molecules to target and suppress immunecells. Blinatumomab (Blincyto®) is such an example. Checkpointinhibitors, such as, for example, ipilumimab, are another such example.The immune effector may be, for example, an antibody specific for somemarker on the surface of a tumor cell. The antibody alone may serve asan effector of therapy or it may recruit other cells to actually affectcell killing. The antibody also may be conjugated to a drug or toxin(chemotherapeutic, radionuclide, ricin A chain, cholera toxin, pertussistoxin, etc.) and serve merely as a targeting agent. Alternatively, theeffector may be a lymphocyte carrying a surface molecule that interacts,either directly or indirectly, with a tumor cell target. Variouseffector cells include cytotoxic T cells and NK cells.

In one aspect of immunotherapy, the tumor cell must bear some markerthat is amenable to targeting, i.e., is not present on the majority ofother cells. Many tumor markers exist and any of these may be suitablefor targeting in the context of the present embodiments. Common tumormarkers include CD20, carcinoembryonic antigen, tyrosinase (p9′7), gp68,TAG-72, HMFG, Sialyl Lewis Antigen, MucA, MucB, PLAP, laminin receptor,erb B, and p155. An alternative aspect of immunotherapy is to combineanticancer effects with immune stimulatory effects. Immune stimulatingmolecules also exist including: cytokines, such as IL-2, IL-4, IL-12,GM-CSF, gamma-IFN, chemokines, such as MIP-1, MCP-1, IL-8, and growthfactors, such as FLT3 ligand.

Examples of immunotherapies currently under investigation or in use areimmune adjuvants, e.g., Mycobacterium bovis, Plasmodium falciparum,dinitrochlorobenzene, and aromatic compounds (U.S. Pat. Nos. 5,801,005and 5,739,169; Hui and Hashimoto, 1998; Christodoulides et al., 1998);cytokine therapy, e.g., interferons α, β, and γ, IL-1, GM-CSF, and TNF(Bukowski et al., 1998; Davidson et al., 1998; Hellstrand et al., 1998);gene therapy, e.g., TNF, IL-1, IL-2, and p53 (Qin et al., 1998;Austin-Ward and Villaseca, 1998; U.S. Pat. Nos. 5,830,880 and5,846,945); and monoclonal antibodies, e.g., anti-CD20, anti-gangliosideGM2, and anti-p185 (Hollander, 2012; Hanibuchi et al., 1998; U.S. Pat.No. 5,824,311). It is contemplated that one or more anti-cancertherapies may be employed with the antibody therapies described herein.

D. Surgery

Approximately 60% of persons with cancer will undergo surgery of sometype, which includes preventative, diagnostic or staging, curative, andpalliative surgery. Curative surgery includes resection in which all orpart of cancerous tissue is physically removed, excised, and/ordestroyed and may be used in conjunction with other therapies, such asthe treatment of the present embodiments, chemotherapy, radiotherapy,hormonal therapy, gene therapy, immunotherapy, and/or alternativetherapies. Tumor resection refers to physical removal of at least partof a tumor. In addition to tumor resection, treatment by surgeryincludes laser surgery, cryosurgery, electrosurgery, andmicroscopically-controlled surgery (Mohs' surgery).

Upon excision of part or all of cancerous cells, tissue, or tumor, acavity may be formed in the body. Treatment may be accomplished byperfusion, direct injection, or local application of the area with anadditional anti-cancer therapy. Such treatment may be repeated, forexample, every 1, 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, 4, and 5weeks or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. Thesetreatments may be of varying dosages as well.

E. Other Agents

It is contemplated that other agents may be included in a drug waferimplant or used in combination with certain aspects of the presentembodiments to improve the therapeutic efficacy of treatment. Theseadditional agents include agents that affect the upregulation of cellsurface receptors and GAP junctions, cytostatic and differentiationagents, inhibitors of cell adhesion, agents that increase thesensitivity of the hyperproliferative cells to apoptotic inducers, orother biological agents. Increases in intercellular signaling byelevating the number of GAP junctions may increase theanti-hyperproliferative effects on the neighboring hyperproliferativecell population. In other embodiments, cytostatic or differentiationagents can be used in combination with certain aspects of the presentembodiments to improve the anti-hyperproliferative efficacy of thetreatments. Inhibitors of cell adhesion are contemplated to improve theefficacy of the present embodiments. Examples of cell adhesioninhibitors are focal adhesion kinase (FAKs) inhibitors and Lovastatin.It is further contemplated that other agents that increase thesensitivity of a hyperproliferative cell to apoptosis, such as theantibody c225, could be used in combination with certain aspects of thepresent embodiments to improve the treatment efficacy.

II. Kits

Certain aspects of the present invention may provide kits, such astherapeutic kits. For example, a kit may comprise one or morepharmaceutical composition as described herein and optionallyinstructions for their use. Kits may also comprise one or more devicesfor accomplishing administration of such compositions. For example, asubject kit may comprise a pharmaceutical composition and wafer orimplant for accomplishing administration of a therapeutic agent into atissue in a subject, e.g., a brain tissue in a resection cavity insubject.

Kits may comprise a container with a label. Suitable containers include,for example, bottles, vials, and test tubes. The containers may beformed from a variety of materials, such as glass or plastic. Thecontainer may hold a composition that includes a polypeptide that iseffective for therapeutic or non-therapeutic applications, such asdescribed above. The label on the container may indicate that thecomposition is used for a specific therapy or non-therapeuticapplication, and may also indicate directions for either in vivo or invitro use, such as those described above. The kit of the invention willtypically comprise the container described above and one or more othercontainers comprising materials desirable from a commercial and userstandpoint, including buffers, diluents, filters, needles, syringes, andpackage inserts with instructions for use.

EXAMPLES

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

Example 1 Multi-Layered Implants

In the following examples, Layer 1 is always the side positionedproximal, or directly against the brain tissue in the resection cavity.

An embodiment of the present invention provides a wafer or compositioncomprising:

Layer 1 Polyethylene oxide 4M 10% Layer 2 80% paxlitaxel 12% glycerylbehenate 60% stearic acid  6% polyethylene oxide 0.9M 22% Layer 3 10%Stearic acid  5% Glyceryl behenate  5%

The components for Layer 2 are first passed through a 60 mesh screen toremove lumps and then blended in a twin shell blender for 5 minutes. Thethree layered wafer is compressed and used a described previously. Thesetechnologies and methods are familiar to a person of ordinary skill inthe art.

A further embodiment of the present invention provides a bilayered waferimplant composition comprises the following ingredients:

Layer 1.   85% carboplatin  7.5% docetaxel 12.5% glycerol behenate   43%polyethylene oxide 1M   37% Layer 2. Stearic Acid   15%

The components of Layer 1 are added first to the die in the tabletpress, followed by the stearic acid. These wafers were compressed andthen heated at 68° C. for 3 hours.

A further embodiment of the present invention for the manufacture ofwafers or tablets, comprises the following composition:

a. temozolomide 75 mg b. stearic acid 25 mg c. lipase  3 mg d.cholesterol 12 mg e. glycerol behenate 70 mg f. poloxamer F-68 15 mg g.polyanhydroglucuronic acid 50 mg

The wafer compositions of this example can be processed according tomethods known to a person who is already skilled in the art asexemplified in Method 1. Using the tablet compression method, thepowders are first passed through a 100 mesh screen and then dry blendedfor 5 minutes prior to compression. Using a Carver press or tabletpress, the components for the drug containing layer are first added tothe tablet die followed by the hydrophobic powder as described inMethod 1. The resulting compositions were then cured at 65° C. for 3hours. Implant compositions were prepared according to the Methods asdescribed below.

The components of the drug containing layers in the compositions ofMethods 2 and 3 can also be processed by injection molding and thenmilled into finer particles prior to compression into wafers that are1.5 cm in diameter and 3 mm thick. The implants are then cured for 2hours at 65° C.

A trilayered implant composition according to the present invention iscomposed of:

Layer 1 polyethylene oxide 1M  40 mg Layer 2 cetuximab  35 mg everolimus 40 mg chitosan  10 mg polyoxyethylene oxide 0.9M  65 mg glycerolbehenate 100 mg Layer 3. Glycerol behenate  20 mg Cholesterol  8 mg

The compressed wafers were cured at 60° C. for 8 hours.

Another preferred embodiment of the present invention has a compositionof:

Layer 1 Chitosan  8% Polyethylene oxide 4M  6% Layer 2 70% cisplatin 20%glyceryl behenate 40% stearic acid 10% polyethylene oxide 0.5M 20%polyanhydroglucuronic acid 10% Layer 3 Glycerol behenate 14%

The polyanhydroglucuronic acid (Surgicel®) was cryogenically processedand then ground into fine powder. The composition is wet granulated withpurified water, dried, passed through a 20 mesh screen and thenprocessed into 500 mg wafers according to the processing methodsoutlined in Method 1. Circular wafers were then cured at 65° C. for 2hours.

Bevacizumab (20% Layer 2) and Methotraxate (20% Layer 2) implants wereprepared according to Method 6 and heat cured at 70° C. for 2 hours.

A further embodiment of the present invention for the manufacture of atrilayered film composition comprising the following ingredients:

Layer 1 Polyethylene oxide 4M  20% Layer 2  70% Irinotecan   8% Lipase0.5% Stearic acid  14% Glyceryl behenate  49% Pitavastatin 3.5%Poloxamer F68  10% Polyethylene oxide 0.9M  15% Layer 3 Glycerylbehenate  10%

A film of polyethylene oxide is prepared by hot melt extrusion atprocess temperatures in the extruder ranging from 75° C. to 95° C. Tothis film, a molten composition is evenly spread and then cooled to roomtemperature. The glyceryl behenate in Layer 3 is melted and added ontothe drug containing layer. The film is cooled and then cut into suitablesized wafers that are then heat cured at 68° C. for 4 hours.

Method 1. An embodiment of the present invention provides a trilayerwafer or composition comprising:

Layer 1 Polyethylene oxide 7M  50 mg Layer 2 200 mg paclitaxel  8 mgglyceryl behenate 185 mg polyethylene oxide 7M  7 mg Layer 3 glycerylbehenate 100 mg

All inert components were passed through a 70 mesh screen. A trilayeredwafer was prepared by first adding the polyethylene oxide 7M (Layer 1)to the tablet die, followed by the powder blend containing paclitaxel,glyceryl behenate and the polyethylene oxide (Layer 2). The glycerylbehenate (Layer 3) was first melted at 120° C., cooled and passedthrough a 60 mesh screen and then added to the die prior to compressioninto a trilayered wafer. The sides of the circular trilayered wafer andthe top lipophilic wax layer (Layer 3) were then coated with moltenglyceryl behenate at 98° C., leaving the bioadhesive layer (Layer 1)uncoated and was then cured at approximately 72° C. for ten minutes.

Method 2. A composition of Method 1 was prepared where the three powdersof the drug containing layer (Layer 2) were blended together and thenmelt granulated by heating the powder blend to approximately 120° C. forfive minutes. The resulting mass was then cooled, milled and passedthrough a 60 mesh screen, before incorporation into the three layerwafer using the method described in Method 1.

Method 3. A further embodiment of the present invention involves thecomposition of Method 1, when the glyceryl behenate and paclitaxel inLayer 2 are first blended together and then melt granulated by heatingthe powder to 120° C. for five minutes. When this mass was cooled andpassed through a 60 mesh screen, the polyethylene oxide component ofLayer 2 was then added to form the final powder blend for Layer 2, whichwas then incorporated into the trilayered wafer formulation and thenprocessed according to the method described in Method 1.

Method 4. A further embodiment of the present invention provides atrilayered wafer implant composition of Method 3 where the sides and toplipophilic layer of the wafer were coated, in lieu of glyceryl behenate,with an organic solution of a Resomer® RG 756 S biodegradable polymer(5% W/W in acetone), (Resomer® RG 756S) leaving the bioadhesive layer(Layer 1), uncoated, and cured at 72° C. for 10 minutes.

Method 5. A further embodiment of the present invention provided acoated three layered wafer composition to contain carboplatin 3 mg, anddocetaxel 5 mg, as the active ingredients in a 350 mg trilayered wafer,prepared by the method outlined in Method 3.

Method 6. A further embodiment of the present invention provides for themanufacture of trilayered wafers each comprising the followingcomposition:

Layer 1 polyethylene oxide 7M  15 mg Layer 2 dexamethasone sodiumphosphate  8 mg paclitaxel  20 mg glyceryl behenate 162 mg stearic acid 7 mg polyethylene oxide7M  8 mg Layer 3 glyceryl behenate 100 mg

All inert components were passed through a 70 mesh screen. Thetrilayered wafer was prepared by first adding the polyethylene oxide 7M(Layer 1) to a tablet die, followed by the powder blend containing thetwo active ingredients, along with the glyceryl behenate and the stearicacid in the Layer 2 composition that had previously been melt granulatedby heating the powders of Layer 2 to 120° C. for five minutes. When thismass was cooled and passed through a 60 mesh screen, the polyethyleneoxide component of Layer 2 was then added to form the final powder blendfor Layer 2, which was then incorporated into the trilayered waferformulation. The melt granulated glyceryl behenate (Layer 3) was thenadded to the die, prior to compression into a trilayered wafer. Thesides of the circular trilayered wafer and the top lipophilic wax layer(Layer 3) were then coated with molten glyceryl behenate leaving thebioadhesive layer (Layer 1) uncoated.

Method 7. A further embodiment of the present invention of compositionin Example 6 provides a trilayered wafer that was cured at approximately72° C. for ten minutes.

Method 8. A further embodiment of the present invention provides for themanufacture of trilayered wafers or tablets each comprising thefollowing composition:

Layer 1. polyethylene oxide 7M  50 mg Layer 2. temozolomide  25 mgstearic acid  25 mg lipase  2 mg cholesterol  10 mg glyceryl behenate105 mg poloxamer F-68  8 mg polyanhydroglucuronic acid  25 mg Layer 3stearic acid  40 mg glyceryl behenate  60 mg

All inert components were passed through a 70 mesh screen, except forthe polyanhydroglucuronic acid which was passed through a 40 meshscreen. A trilayered wafer was prepared by first adding the polyethyleneoxide 7M (Layer 1) to the tablet die, followed by the powders of thedrug containing layer (Layer 2), which had been previously blendedtogether and wet granulated with water and then melt granulated byheating the powder blend to approximately 120° C. for five minutes. Theresulting mass was then cooled and milled before passing through a 40mesh screen. The powder blend of stearic acid and glyceryl behenate(Layer 3) was melt granulated and cooled before passing through a 60mesh screen and then added to the die prior to compression into atrilayered wafer. The sides and the top lipophilic wax layer (Layer 3)of the circular trilayered wafer were then coated with molten glycerylbehenate, leaving the bioadhesive layer (Layer 1) uncoated. The coatedwafer was then cured at approximately 74° C. for 8 minutes.

Method 9. A further embodiment of the present invention provides for theuncoated trilayered wafer of Method 6, to contain irinotecan 12 mg inplace of the temozolomide. The sides and the top lipophilic wax layer(Layer 3) of the trilayered wafer were then coated with a 5% w/w acetonesolution of PLGA (Resomer® RG 756S), and cured at 60° C. for eightminutes.

Method 10. A further embodiment of the present invention provides forthe manufacture of trilayered wafers, each comprising the followingcomposition as described below.

Layer 1 chitosan 30 mg polyethylene glycol 100,000 5 mg polyethyleneoxide 1M 15 mg Layer 2 carboplatin 3 mg atorvastin 1.5 mg cisplatin 4 mgstearic acid 212 mg lipase 1.5 mg glyceryl tristearate 20 mgpolyethylene oxide 0.9M 8 mg Layer 3 stearic acid 20 mg glycerylbehenate 80 mg

All inert components were prescreened to remove lumps and aggregates. Atrilayered wafer was prepared by first blending the components of Layer1, including chitosan, polyethylene glycol, and polyethylene oxide, intoa uniform composition. This material was then added to the tablet die.

The three active ingredients in Layer 2, were blended together and thenincorporated with the remaining powders in Layer 2 and melt granulatedby heating the powder blend to approximately 120° C. for ten minutes.

The resulting mass was cooled and milled by passing through a 60 meshscreen. The granulation from Layer 2 was then added to the tablet die,followed by the stearic acid and glyceryl behenate melt granulatedpowder blend that formed Layer 3, prior to compression.

The sides of the circular trilayered wafer and the top lipophilic waxlayer (Layer 3) were then coated with molten glyceryl behenate, leavingthe bioadhesive layer (Layer 1) uncoated. The coated wafers were thenheat treated at 60° C. for 5 minutes.

Method 11. A further embodiment of the present invention provides abilayered wafer implant composition comprised of the followingingredients:

Layer 1 carboplatin  7 mg docetaxel  4 mg glyceryl behenate 214 mgpolyethylene oxide 7M  13 mg lipase  2 mg Layer 2 palmitic acid  48 mgglyceryl behenate 112 mg

The inert components of Layer 1 were dry blended and then passed throughan 70 mesh screen. Using water as the granulating agent, the powderblend was then wet granulated. The granules were dried for four hours at60° C., were passed through a 60 mesh screen and then melt granulated byheating the power blend at 110° C. for four minutes. The resulting masswas cooled and then passed through a 30 mesh screen. The bilayeredwafers were prepared by adding the components from Layer 1 to the tabletdie, followed by the powder from Layer 2 to the tablet die, incompositions as described above. The bilayered wafers were thencompressed and cured at 62° C. for eight minutes.

Method 12. A further example of the present invention provides for theuncoated bilayered wafers of Method 11 to have the sides and the toplipophilic wax layer (Layer 2) of the bilayered wafer coated with moltenglyceryl behenated, leaving the bioadhesive layer (Layer 1) uncoated.The coated wafers were then heat treated at 70° C. for 5 minutes.

Method 13. A further embodiment of the present invention provides abilayered wafer implant composition comprised of the followingingredients:

Layer 1 paclitaxel  11 mg dexamethasone sodium phosphate  7 mg glycerylbehenate 207 mg polyethylene oxide 7M  13 mg lipase  2 mg Layer 2palmitic acid  48 mg glyceryl behenate 112 mg

The inert components of Layer 1 were dry blended and then passed throughan 70 mesh screen. Using water as the granulating agent, the powderblend was then wet granulated. The dried granules were passed through a60 mesh screen and then melt granulated by heating the power blender110° C. for four minutes. The resulting mass was cooled and then passedthrough a 30 mesh screen. The bilayered wafers were prepared by addingthe components from Layer 1 to the tablet die, followed by the meltgranulated powder from Layer 2 to the tablet die, in compositions asdescribed above. The bilayered wafers were then compressed and heated at70° C. for eight minutes.

Method 14. A further example of the present invention provides for theuncoated trilayered wafers of Method 9 to have the sides and the toplipophilic wax layer (Layer 2) of the bilayered wafer coated with moltenglyceryl behenated, leaving the bioadhesive layer (Layer 1) uncoated.The coated wafers were then heat treated at 70° C. for 5 minutes.

Method 15. A further embodiment of the present invention provides atrilayered implant composition comprising the following ingredients:

Layer 1 polyethylene oxide 1M 15 mg Polyethylene oxide 7M 35 mg Layer 2bevacizumab 2 mg cetuximab 1.5 mg everolimus 4.5 mg glyceryl behenate185 mg polyethylene oxide 7 mg (100,000 MW) Layer 3 glyceryl behenate 85mg stearic acid 10 mg Cholesterol 5 mg

All inert components are first prescreened to remove lumps andaggregates. A trilayered wafer is prepared by first blending the twocomponents of Layer 1 into a uniform composition. 50 mg of this materialis then added to the tablet die.

The three active ingredients in Layer 2 are blended and then furthermixed with the glyceryl behenate and the polyethylene oxide excipients.This powder is then melted granulated by heating the powder blend toapproximately 100° C. for six minutes.

The resulting mass is then cooled and milled by passing through a 60mesh screen. 200 mg of this granulation is then added to the tablet die,followed by 100 mg of the granulated blended ingredients comprisingLayer 3. The sides of the circular trilayered compressed wafer and thetop lipophilic wax layer (Layer 3) are then coated with molten glycerylbehenate, leaving the bioadhesive layer (Layer 1) uncoated. The coatedwafers are then heat treated at 72° C. for four minutes.

Method 16. A further embodiment of the present invention for themanufacture of a trilayered film comprises the following ingredients:

Layer 1 polyethylene oxide 4M  20% Layer 2 epirubicin HCl   8% lipase0.5% stearic acid  14% glyceryl behenate  49% pitavastatin 3.5%poloxamer F68  10% polyethylene oxide 0.9M  15% Layer 3 glycerylbehenate  10%

A film of polyethylene oxide is prepared by hot melt extrusion atprocessing temperatures in the extruder ranging from 75° C. to 140° C.To this film, a molten composition of Layer 2 is evenly spread and thencooled to room temperature. The glyceryl behenate in Layer 3 is meltedand added onto the drug containing layer. The film is cooled and thencut into suitable sized wafers that are then heat cured at 68° C. for 4hours.

Method 17: A further embodiment of the present invention provides forthe manufacture of trilayered wafers comprised of the followingcomposition:

Layer 1 polyethylene oxide 7M  15 mg Layer 2 methotrexate  10 mgdexamethasone sodium phosphate  15 mg glyceryl behenate 158 mg stearicacid  14 mg polyethylene oxide 7M  8 mg Layer 3 glyceryl behenate 100 mg

All inert components were passed through a 70 mesh screen. Thetrilayered wafer was prepared by first adding the polyethylene oxide 7M(Layer 1) to a tablet die. The powder blend containing the dexamethasonesodium phosphate and methotrexate was added to the glyceryl behenate andthe stearic acid in the Layer 2 composition. The two lipids hadpreviously been melt granulated by heating the powders of Layer 2 to110° C. for five minutes. When this mass had been cooled and passedthrough a 60 mesh screen, the polyethylene oxide component of Layer 2was then added to form the final powder blend for Layer 2, which wasthen incorporated into the trilayered wafer formulation. The meltgranulated glyceryl behenate (Layer 3) was then added to the die, priorto compression into a trilayered wafer. The sides of the circulartrilayered wafer and the top lipophilic wax layer (Layer 3) were thencoated with molten glyceryl behenate at approximately 90° C., leavingthe bioadhesive layer (Layer 1) uncoated and then cured at approximately72° C. for ten minutes.

Method 18: A further embodiment of the present composition provides forthe manufacture of trilayered wafers comprising carmustine as the activeingredient using the composition and method of preparation as describedbelow.

Layer 1 polyethylene oxide 7M  50 mg Layer 2 carmustine  20 mg glycerylbehenate 174 mg polyethylene oxide 7M  6 mg Layer 3 Glyceryl behenate100 mg

All inert components are passed through an 80 mesh screen. Thetrilayered wafer is prepared by first adding the polyethylene oxide 7M(Layer 1) to a tablet die. The powder blend containing the carmustine isadded to the glyceryl behenate in the Layer 2 composition. The lipid ismelt granulated by heating the powders of Layer 2 to 90° C. for twominutes. When this mass is cooled and passed through a 60 mesh screen,the polyethylene oxide component of Layer 2 is then added to form thefinal powder blend for Layer 2 and is added to the die. Then the meltgranulated glyceryl behenate (Layer 3) is added to the die, prior tocompression into a trilayered wafer. The sides of the circulartrilayered wafer and the top lipophilic wax layer (Layer 3) were thencoated with molten glyceryl behenate leaving the bioadhesive layer(Layer 1) uncoated and then cured at approximately 72° C. for tenminutes.

Method 19: A further embodiment of the present composition provides forthe manufacture of trilayered wafers comprising doxorubicin as theactive ingredient using the composition and method of preparation asdescribed below.

Layer 1 polyethylene oxide 7M 25 mg Layer 2 doxorubicin 25 mg glycerylbehenate 170 mg polyethylene oxide 7M 5 mg Layer 3 Glyceryl behenate 50mg

All inert components are passed through an 80 mesh screen. Thetrilayered wafer is prepared by first adding the polyethylene oxide 7M(Layer 1) to a tablet die. The powder blend containing the doxorubicinis added to the glyceryl behenate in the Layer 2 composition. The lipidand drug are melt granulated by heating the powders of Layer 2 to 90° C.for one minute. When this mass is cooled and passed through a 60 meshscreen, the polyethylene oxide component of Layer 2 is then added toform the final powder blend for Layer 2 and is added to the die. Thenthe melt granulated glyceryl behenate (Layer 3) is added to the die,prior to compression into a trilayered wafer. The sides of the circulartrilayered wafer and the top lipophilic wax layer (Layer 3) are thencoated with molten glyceryl behenate leaving the bioadhesive layer(Layer 1) uncoated and then cured at approximately 70° C. for fifteenminutes.

Method 20: A further embodiment of the present composition provides forthe manufacture of trilayered wafers comprising topotecan as the activeingredient using the composition and method of preparation as describedin Method 19.

Layer 1 polyethylene oxide 7M  25 mg Layer 2 topotecan  10 mg glycerylbehenate 182 mg polyethylene oxide 7M  8 mg Layer 3 Glyceryl behenate 75 mg

All inert components are passed through an 80 mesh screen. Thetrilayered wafer is prepared by first adding the polyethylene oxide 7M(Layer 1) to a tablet die. The powder blend containing the topotecan isadded to the glyceryl behenate in the Layer 2 composition. The lipid anddrug are melt granulated by heating the powders of Layer 2 to 90° C. forone minute. When this mass is cooled and passed through a 60 meshscreen, the polyethylene oxide component of Layer 2 is then added toform the final powder blend for Layer 2 and is added to the die. Then,melt granulated glyceryl behenate (Layer 3) is added to the die, priorto compression into a trilayered wafer. The sides of the circulartrilayered wafer and the top lipophilic wax layer (Layer 3) are thencoated with molten glyceryl behenate leaving the bioadhesive layer(Layer 1) uncoated and then cured at approximately 73° C. for tenminutes.

Method 21: A further embodiment of the present composition provides forthe manufacture of trilayered wafers comprising D-actinomycin as theactive ingredient using the composition and method of preparation asdescribed in Method 19.

Layer 1 polyethylene oxide 7M  35 mg Layer 2 D-actinomycin  10 mgglyceryl behenate 182 mg polyethylene oxide 7M  7 mg Layer 3 Glycerylbehenate 100 mg

All inert components are passed through an 80 mesh screen. Thetrilayered wafer is prepared by first adding the polyethylene oxide 7M(Layer 1) to a tablet die. The powder blend containing the D-actinomycinis added to the glyceryl behenate in the Layer 2 composition. The lipidand drug are melt granulated by heating the powders of Layer 2 to 90° C.for one minute. When this mass is cooled and passed through a 60 meshscreen, the polyethylene oxide component of Layer 2 is then added toform the final powder blend for Layer 2 and is added to the die. Then,melt granulated glyceryl behenate (Layer 3) is added to the die, priorto compression into a trilayered wafer. The sides of the circulartrilayered wafer and the top lipophilic wax layer (Layer 3) are thencoated with molten glyceryl behenate leaving the bioadhesive layer(Layer 1) uncoated.

Method 22: A further embodiment of the present composition provides forthe manufacture of trilayered wafers comprising a copper chelating agentsuch as D-penicillamine as the active ingredient using the compositionand method of preparation as described in Method 19.

Layer 1 polyethylene oxide 7M  50 mg Layer 2 D-penicillamine  40 mgglyceryl behenate 156 mg polyethylene oxide 1M  4 mg Layer 3 Glycerylbehenate 100mg

All inert components are passed through an 80 mesh screen. Thetrilayered wafer is prepared by first adding the polyethylene oxide 7M(Layer 1) to a tablet die. The powder blend containing theD-penicillamine is added to the glyceryl behenate in the Layer 2composition. The lipid and drug are melt granulated by heating thepowders of Layer 2 to 90° C. for one minute. When this mass is cooledand passed through a 60 mesh screen, the polyethylene oxide component ofLayer 2 is then added to form the final powder blend for Layer 2 and isadded to the die. Then, melt granulated glyceryl behenate (Layer 3) isadded to the die, prior to compression into a trilayered wafer. Thesides of the circular trilayered wafer and the top lipophilic wax layer(Layer 3) are then coated with molten glyceryl behenate leaving thebioadhesive layer (Layer 1) uncoated.

Method 23: A further embodiment of the present composition provides forthe manufacture of trilayered wafers comprising a copper chelating agentsuch as D-penicillamine and paclitaxel as the active ingredient usingthe composition and method of preparation as described below.

Layer 1 polyethylene oxide 7M  50 mg Layer 2 D-penicillamine  30 mgPaclitaxel  10 mg glyceryl behenate 156 mg polyethylene oxide 1M  4 mgLayer 3 Glyceryl behenate 100 mg

All inert components are passed through an 80 mesh screen. Thetrilayered wafer is prepared by first adding the polyethylene oxide 7M(Layer 1) to a tablet die. The powder blend containing theD-penicillamine and paclitaxel is added to the glyceryl behenate in theLayer 2 composition. The lipid and drugs are melt granulated by heatingthe powders of Layer 2 to 90° C. for one minute. When this mass iscooled and passed through a 60 mesh screen, the polyethylene oxidecomponent of Layer 2 is then added to form the final powder blend forLayer 2 and is added to the die. Then, melt granulated glyceryl behenate(Layer 3) is added to the die, prior to compression into a trilayeredwafer. The sides of the circular trilayered wafer and the top lipophilicwax layer (Layer 3) are then coated with molten glyceryl behenateleaving the bioadhesive layer (Layer 1) uncoated.

Method 24: A further embodiment of the present composition provides forthe manufacture of trilayered wafers comprising a synthetic alkyllysophospholipid such as edelfosine and paclitaxel as the activeingredients using the composition and method of preparation as describedbelow.

Layer 1 polyethylene oxide 7M  50 mg Layer 2 Edelfosine  1 mg Paclitaxel 10 mg glyceryl behenate 182 mg polyethylene oxide 1M  7 mg Layer 3Glyceryl behenate 100 mg

All inert components are passed through an 80 mesh screen. Thetrilayered wafer is prepared by first adding the polyethylene oxide 7M(Layer 1) to a tablet die. The powder blend containing the edelfosineand paclitaxel is added to the glyceryl behenate in the Layer 2composition. The lipid and drugs are melt granulated by heating thepowders of Layer 2 to 90° C. for one minute. When this mass is cooledand passed through a 60 mesh screen, the polyethylene oxide component ofLayer 2 is then added to form the final powder blend for Layer 2 and isadded to the die. Then, melt granulated glyceryl behenate (Layer 3) isadded to the die, prior to compression into a trilayered wafer. Thesides of the circular trilayered wafer and the top lipophilic wax layer(Layer 3) are then coated with molten glyceryl behenate leaving thebioadhesive layer (Layer 1) uncoated.

Method 25: A further embodiment of the present composition provides forthe manufacture of trilayered wafers comprising a bioactive sulfatedsaponin such as Sponin-1 (SAP-1) as the active ingredient using thecomposition and method of preparation as described below.

Layer 1 polyethylene oxide 7M  50 mg Layer 2 SAP-1  30 mg glycerylbehenate 166 mg polyethylene oxide 1M  4 mg Layer 3 Glyceryl behenate100 mg

All inert components are passed through an 80 mesh screen. Thetrilayered wafer is prepared by first adding the polyethylene oxide 7M(Layer 1) to a tablet die. The powder blend containing SAP-1 is added tothe glyceryl behenate in the Layer 2 composition. The lipid and drug arephysically blended with the polyethylene oxide component of Layer 2 toform the final powder blend for Layer 2 and is added to the die. Then,melt granulated glyceryl behenate (Layer 3) is added to the die, priorto compression into a trilayered wafer. The sides of the circulartrilayered wafer and the top lipophilic wax layer (Layer 3) are thencoated with molten glyceryl behenate leaving the bioadhesive layer(Layer 1) uncoated.

Example 2 Generation of Multi-Layered Implants and PhysiochemicalProperties

Materials and Methods

Materials:

Acetaminophen, USP, was purchased from Spectrum Chemical (Gardena,Calif., USA). Compritol 888 ATO was generously provided by Gattefosse(Paramus, N.J., USA). Poly(ethylene oxide) was generously donated inthree different grades (PolyOx N10, N12K, and 303) by Dow Chemical(Midland, Mich., USA). All other chemicals utilized in this study wereof ACS grade.

Dispersion of Acetaminophen in Compritol®:

Acetaminophen and Compritol® were passed through a 70 mesh stainlesssteel screen prior to use. Homogenous blends of Compritol® andacetaminophen were prepared via geometric dilution using a mortar andpestle. The blend was placed for 5 minutes inside an oven set at 80° C.to melt Compritol®. Under constant mixing of a stirring rod, dispersionof acetaminophen in the molten Compritol® was poured onto an aluminumtray to allow Compritol® to solidify at ambient conditions. Thesolidified wax was ground up into small granules using a mortar andpestle. The granules were then passed through a 60 mesh stainless screento obtain a dispersion of acetaminophen in Compritol®.

Preparation of Acetaminophen Wafers for Implant:

Three types of implant wafers, single layer, bilayer and tri-layer, wereprepared in this study. As shown in FIG. 1, single layer wafer contained200 mg drug layer only. Bilayer wafer was consisting of a 200 mg druglayer and 100 mg Compritol layer. In tri-layer wafer, 200 mg drug layeris sandwiched between 100 mg Compritol layer and 50 mg PolyOx layer.

An 11 mm in diameter, round and flat-faced tableting tooling was used toprepare the wafers. Powder blends for each individual layer were filledinto die on a layer by layer fashion. The powder was compressed with aCarver press (Model MTCM-1, Globepharma, New Brunswick, N.J., US). Thecompression force was kept at 3000 psi.

Coating and Curing of Wafers for Implant:

Wafers were coated with a hydrophobic wax or polymer. Curing of waferswas performed using the column oven in a gas chromatography system(Agilent, Model GC 7820A, Santa Clara, Calif. US). The wafers were curedat 73° C. for a total of 10 minutes.

In Vitro Drug Release Testing:

Each implant was placed inside a 20 mL glass scintillation vial. Twentymilliliter 50 mM phosphate buffer pH 7.4 was added into each vial as thedissolution medium. The vials were stored inside an incubator chamberset at 37° C. Three milliliter dissolution medium was sampled atpre-determined time points. The buffer solution was used to replace thedissolution medium withdrawn at the time of sampling.

HPLC for the Quantitation of Acetaminophen in Dissolution Samples:

Dissolution samples were analyzed using a reversed phase HPLC method.Poroshell® 120, EC-C18, 2.7 4.6×50 mm (Agilent, Santa Clara, Calif.,USA) was used as the HPLC column. A mixture of water and acetonitrilemixture (95:5 ratio) containing 0.05% trifluoroacetic acid was used asthe mobile phase. The flow rate was set at 1.0 mL/min and the injectionvolume was 10 μL. A UV detector (Waters® 2998 PDA detector, Milford,Mass.) was used to quantitate at 275 nm. The retention time ofacetaminophen was 2.1 minutes.

Differential Scanning Thermal Analysis:

Differential scanning calorimetry testing was performed using a TAThermal Analyzer (Model DSC Q20, TA Instruments, New Castle, Del., US).The temperature was calibrated with an indium standard. Sample size wasabout 5 mg and a temperature ramp of 10° C. per minute was used.Universal Analysis 2000 data analysis software was used for dataanalysis. Inflection point method was used for the analysis of the glasstransition temperature. The melting temperature is defined as theintersection of the extension of the baseline with the tangent at theinflection point of the curve.

Powder X-Ray Diffraction:

Powder X-ray diffraction (PXRD) was performed using a Rigaku Miniflexinstrument (Rigaku, Woodlands, Tex., US). A Cu Kα (X=1.54 A) radiationwith Ni filter, was used with a voltage of 40 kV, and a current of 100mA. Samples of powder were placed into channeled stage and continuousscans were made from 10° to 40° 20 with a step size of 0.05°.

Scanning Electron Microscopy:

Scanning electron microscopy (SEM) was performed according toestablished protocols.

Results from these experiments are shown in FIGS. 1-6. As shown in thefigures drug release from the wafers was observed over a period of days.It is anticipated that this pharmacokinetic profile may beadvantageously used to deliver a therapeutic compound to the brain.

As shown in FIG. 1, release of acetaminophen (APAP) from single layer(drug layer only) wafer was observed. Composition: 5% APAP, certainpercent of PEO 303 (7,000,000 molar mass), and glycerol behenate q.s. to100%, a total of 200 mg. Objective: to investigate the percent of PEO ondrug release from drug layer only wafer. Conclusion: levels of PEO 303between 1.5 and 4% were observed to be particularly effective.

Additional results are shown in FIGS. 2-6. A diagram of a multi-layeredimplant is shown in FIG. 7. Effect of the Molecular Weight and Percentof PolyOx on Drug Release from Coated Bilayer Wafer Implants wasevaluated (N10, N12K and 303 at 0, 1.5 and 3.0%, w/w Lot 15-). Effect ofthe Molecular Weight and Percent of PolyOx on Drug Release from CoatedBilayer Wafer Implants (N10, N12K and 303 at 0, 4.0 and 5.0%, w/w Lot16-) was evaluated. Effect of wax coating and bioadhesive layer on drugrelease from wafers (3% 303, 17-1: single layer; 17-3: coated bilayer;17-5: coated tri-layer) was evaluated. Effect of curing was evaluated.Solubility of APAP in Compritol wax was evaluated.

DSC results are shown in FIG. 6. Objective: analyze the physical stateof APAP in glycerol behenate, Is APAP completed dissolved at molecularlevel or dispersed as crystalline particles? Conclusion: APAP isdispersed as crystalline particles. Physical blend: 5% APAP+95% glycerolbehenate. Melt mix: 5% APAP+95% glycerol behenate processed using themelt granulation process. Compritol 888: glycerol behenate raw material,used as the reference. APAP: drug substance, used as the control.

All of the methods disclosed and claimed herein can be made and executedwithout undue experimentation in light of the present disclosure. Whilethe compositions and methods of this invention have been described interms of preferred embodiments, it will be apparent to those of skill inthe art that variations may be applied to the methods and in the stepsor in the sequence of steps of the method described herein withoutdeparting from the concept, spirit and scope of the invention. Morespecifically, it will be apparent that certain agents which are bothchemically and physiologically related may be substituted for the agentsdescribed herein while the same or similar results would be achieved.All such similar substitutes and modifications apparent to those skilledin the art are deemed to be within the spirit, scope and concept of theinvention as defined by the appended claims.

REFERENCES

The following references, to the extent that they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated herein by reference.

-   U.S. Pat. No. 8,821,913 B2, “Controlled Releases System Containing    Temozolomide”, Y Wang, D. Fei, Sep. 2, 2014-   D. Zhang, A. Tian. X. Xue, M. Wang, B. Qui, A. Wu, “The Effect of    Temozolommide/Poly(lactide-co-glycolide) (PLGA)/Nano-Hydroxyapatite    Microspheres on Glioma U87 Cells Behavior”, International Journal of    Molecular Sciences, 13(1), p 1109-1125, 2012.-   U.S. Pat. No. 3,364,200, “Oxidized Cellulose Product and Method for    Preparing the Same”, W. Ashton, C. Moser, Jan. 16, 1968.-   M. Aburahma, S. Badr-Eldin, “Compritol 888 ATO: A Multifactional    Lipid Excipient in Drug Delivery Systems and Nanopharmaceuticals”,    Expert Opinion on Drug Delivery, 11(12), p 1865-1883, 2014.-   F. Kreye, F. Siepmann, J. Siepmann, “Drug Release Mechanisms of    Compressed Lipid Implants”, International Journal of Pharmaceutics,    404(1-2), p 27-35, 2011.-   K. Forier, K. Raemdonch, S. De Smedt, J. Demeester, T. coenye, K.    Braeckmans, “Lipid and Polymer Nanoparticles for Drug Delivery to    Bacterial Biofilms”, Journal of Controlled Release, 190, p 607-623,    2014.-   K. Cho, X. Wang, S. Nie, Z. Chen, D. Shin, “Therapeutic Nanoparticle    for Drug Delivery in Cancer”, Clinical Cancer Research, 14, p 1310,    2008.-   S. Kalepu, M. Manthina. V. Padavala, “Oral Lipid-Based Drug Delivery    Systems—An Overview”, Acta Pharmaceutica Sinica B, 3(6), p 361-372,    2013.-   S. Zara, M. Nabila, “Optimizing Oral Drug Delivery Using Lipid Based    Formulations”, International Research Journal of Pharmacy, 5(7),    2014.-   M. Schwab, G. Sax, S. Schulze, G. Winter, “Studies on the Lipase    Induced Degradation of Lipid Based Drug Delivery Systems”, Journal    of Controlled Release, 140, p 27-33, 2009.-   F. Kreye, F. Siepmann, J. Siepmann, “Lipid Implants as Drug Delivery    Systems”, Expert Opinion Drug Delivery, 5(3), p 291-307, 2008.-   L. Zhu, V. Kumar, G. Banker, “Examination of Aqueous Oxidized    Cellulose Dispersions as a Potential Drug Carrier. I. Preparation    and Characterization of Oxidized Cellulose-Phenylpropanolamine    Complexes”, AAPS Pharm Sci Tech, 5(4), p 138-144, 2004.-   U.S. Pat. No. 6,488,963 B1, J. McGinity and F. Zhang, “Hot-Melt    Extrudable Pharmaceutical Formulation”, Dec. 3, 2002.-   M. Masserini, “Nanoparticles for Brain Drug Delivery”, International    Scholarly Research Notices Biochemistry, 2013, Article ID 238428,    2013.-   P. Menei, C. Montero-Menei, M. C. Venier, J. P Benoit, “Drug    Delivery into the Brain Using Poly(lactide-co-glycolide)    Microspheres”, Expert Opinion Drug Delivery, 2(2), 363-376, 2005.-   C. Carbone, A. Campisi, T. Musumeci, G. Raciti, R. Bonfanti, G.    Puglisi, “FA-Loaded Lipid Drug Delivery Systems: Preparation,    Characterization and Biological Studies”, European Journal    Pharmaceutical Sciences, 14(52) p 12-20, 2014.-   I. Shapira, D. Budman, T. Bradley, R. Gralla, “Evolving Lipid-Based    Delivery Systems in the Management of Neoplastic Disease”, Oncology    Reviews, 113, 2009.-   R. Upadhyay, “Drug Delivery Systems, CNS Protection, and the Blood    Brain Barrier”, Bio Med Research International, 2014, Article ID    869269, 2014.-   W. Pardridge, “Drug Delivery to the Brain”, Journal of Cerebral    Blood Flow & Metabolism, 17, p 713-′731, 1997.-   R. Gabathuler, “Approaches to Transport Therapeutic Drugs Across the    Blood-Brain Barrier to Treat Brain Diseases”, Neurobiology of    Disease, 37, p 48-57, 2010.-   G. Tiwari, R. Riwari, B. Sriwastawa, L. Bhati, S. Pandey, S.    Bannerjee, “Drug Delivery Systems: An Updated Review, International    Journal of Pharmaceutical Investigation, 2(1), p 2-11, 2012.-   P. Jiang, R. Mukthavavam, Y. Chao, I. Bharati, V. Fogal, S.    Pastorino, X. Cong, N. Nomura, M. Gallagher, T. Abbas, S. Vali, S.    Pingle, M. Makale, S. Kesari, “Novel Anti-glioblastoma Agents and    Therapeutic Combinations Identified from a Collection of FDA    Approved Drugs”, Journal of Translational Medicine, 12, 2014.-   U.S. Patent Publication No. 2004/0005647-   U.S. Patent Publication No. 2006/0034925-   U.S. Patent Publication No. 2006/0115537-   U.S. Patent Publication No. 2006/0223114-   U.S. Patent Publication No. 2006/0234299-   U.S. Patent Publication No. 2007/0148095-   U.S. Patent Publication No. 2012/0141550-   U.S. Patent Publication No. 2013/0138032-   U.S. Patent Publication No. 2014/0024610-   U.S. Pat. No. 5,739,169-   U.S. Pat. No. 5,801,005-   U.S. Pat. No. 5,824,311-   U.S. Pat. No. 5,830,880-   U.S. Pat. No. 5,846,945-   U.S. Pat. No. 6,232,287-   U.S. Pat. No. 6,528,481-   U.S. Pat. No. 7,452,964-   U.S. Pat. No. 7,671,010-   U.S. Pat. No. 7,781,565-   U.S. Pat. No. 8,507,445-   U.S. Pat. No. 8,450,278-   PCT Publication No. 2008/121949-   PCT Publication No. 2011/053435-   PCT Publication No. 2014/087413-   Anderson, N. G., Practical Process Research & Development—A Guide    For Organic Chemists, 2^(nd) ed., Academic Press, New York, 2012.-   Austin-Ward and Villaseca, Rev. Med. Chil., 126(7):838-45, 1998.-   Barclay et al. (eds.), The Leucocyte Antigen Facts Book, 1993,    Academic Press.-   Bukowski et al., Clin. Cancer Res., 4(10):2337-47, 1998.-   Burkly et al.: TWEAKing tissue remodeling by a multifunctional    cytokine: role of TWEAK/Fn14 pathway in health and disease. Cytokine    40:1-16 (2007).-   Campbell et al., Cancer Res., 51(19):5329-5338 1991.-   Christodoulides et al., Microbiology, 144(Pt 11):3027-37, 1998.-   Davidson et al., J. Immunother 21(5):389-98, 1998.-   Hanibuchi et al., Int. J. Cancer, 78(4):480-485, 1998.-   Hellstrand et al., Acta Oncol., 37(4):347-353, 1998.-   Hui and Hashimoto, Infect. Immun., 66(11):5329-36, 1998.-   Ju et al., Gene Ther., 7(19):1672-1679, 2000.-   March's Advanced Organic Chemistry: Reactions, Mechanisms, and    Structure, 2007.-   Mitchell et al., Ann. NY Acad. Sci., 690:153-166, 1993.-   Mitchell et al., J. Clin. Oncol., 8(5):856-869, 1990.-   Morton et al., Arch. Surg., 127:392-399, 1992.-   Nechushtan et al., 1997-   Onda et al., Cancer Res., 64:1419-1424, 2004.-   Pietras et al., Oncogene, 17(17):2235-49, 1998.-   Qin et al., Proc. Natl. Acad. Sci. USA, 95(24):14411-14416, 1998.-   Ravindranath and Morton, Intern. Rev. Immunol., 7: 303-329, 1991.-   Remington's Pharmaceutical Sciences, 15^(th) Ed., 1035-1038 and    1570-1580, 1990.-   Remington's Pharmaceutical Sciences, 15^(th) Ed., 3:624-652, 1990.-   Rosenberg et al., Ann. Surg. 210(4):474-548, 1989.-   Rosenberg et al., N. Engl. J. Med., 319:1676, 1988.-   Thompson (ed.), 1994, The Cytokine Handbook, Academic Press, San    Diego.-   Weitman et al., Cancer Res., 52(12):3396-3401, 1992b.-   Weitman et al., Cancer Res., 52(23):6708-6711, 1992a.-   Winkles, Nat Rev Drug Discov 7:411-425 (2008).-   Winthrop et al., Clin. Cancer Res., 9:3845s-3853s, 2003.-   Zhou, Mol Cancer Ther. 10(7):1276-88, 2011.

1. A biocompatible drug delivery implant for positioning adjacent to abiological tissue for delivering one or more drugs thereto, the implantcomprising at least two layers, a drug-containing layer having a drugelution surface to be positioned proximal to the tissue, and, a furtherlayer or layers comprising a lipophilic backing layer and/or ahydrophobic coating, said further layer or layers being positioneddistal to the drug elution surface, wherein: a) the drug-containinglayer comprises one or more drugs, a hydrophilic polymer or pore formingagent, and glyceryl behenate; b) the lipophilic backing layer comprisesglyceryl behenate; and c) the hydrophobic coating comprises glycerylbehenate and coats surfaces of the implant that are not to be positionedproximal to the tissue and; and further, when each of layers a), b) andc) are present, the lipophilic backing layer is positioned between thedrug-containing layer and the hydrophobic coating; and wherein the drugis paclitaxel or layer a) comprises dexamethasone.
 2. The implant ofclaim 1, comprising layers a) and b).
 3. The implant of claim 1,comprising layers a) and c).
 4. The implant of claim 1, comprisinglayers a), b) and c).
 5. The implant of claim 1, wherein the implantfurther comprises a drug-permeable, hydrophilic layer d) positionedbetween the drug elution surface of the drug-containing layer and to bepositioned proximal to the tissue. 6-8. (canceled)
 9. The implant ofclaim 5, wherein the layer d) contains a steroid.
 10. The implant ofclaim 9, wherein the steroid is dexamethasone. 11.-20. (canceled) 21.The implant of claim 1, wherein the hydrophilic polymer present in layera) and/or d) is a polyether or a polysaccharide.
 22. The implant ofclaim 21, wherein the hydrophilic polymer is a polyethylene oxide,polypropylene oxide, or a polyethylene glycol.
 23. The implant of claim22, wherein the hydrophilic polymer is a polyethylene oxide.
 24. Theimplant of claim 21, wherein the hydrophilic polymer is apolysaccharide.
 25. The implant of claim 21, wherein the polysaccharideis chitosan or polyanhydroglucuronic acid.
 26. The implant according toclaim 21, wherein the hydrophilic polymer comprises a mixture of apolyether and a polysaccharide.
 27. The implant of claim 26, wherein thehydrophilic polymer is a mixture comprising polyethylene oxide andchitosan.
 28. The implant of claim 21, wherein the hydrophilic polymeris polyethylene oxide or polyanhydroglucuronic acid.
 29. The implant ofclaim 21, wherein the hydrophilic polymer is polyethylene oxide,chitosan, povidone (PVP or polyvinylpyrrolidone), orpolyanhydroglucuronic acid. 30-31. (canceled)
 32. The implant of claim1, wherein the drug is paclitaxel. 33-37. (canceled)
 38. The implant ofclaim 1, wherein layer a) comprises dexamethasone or dexamethasonesodium phosphate.
 39. (canceled)
 40. The implant of claim 1, wherein theimplant is substantially circular or elliptical in shape.
 41. Theimplant of claim 1, wherein the implant is further defined as a wafer.42. The implant of claim 41, wherein the wafer or tablet is configuredfor insertion into a resection cavity.
 43. The implant of claim 1,wherein the implant or wafer further comprises an additional therapeuticagent.
 44. The implant of claim 43, wherein the additional therapeuticagent is an antibiotic, an antimicrobial agent, a statin, an anti-fungalagent, an anti-viral agent, a steroid, an anesthetic, a localanesthetic, or a NSAID.
 45. The implant of claim 44, wherein theadditional therapeutic agent is an antibiotic or an antimicrobial agent.46. The implant of claim 1, wherein the implant does not contain anorganic solvent.
 47. The implant of claim 1, wherein the implantcontains an organic solvent.
 48. The implant of claim 47, wherein theimplant contains no more than a trace amount or a residual amount of theorganic solvent.
 49. The implant of claim 46, wherein the organicsolvent is ethanol, dichloromethane, acetone, tetrahydrofuran, or ethylacetate.
 50. The implant of claim 1, wherein the drug-containing layercomprises glyceryl behenate, stearic acid, polyanhydroglucuronic acid,or polyethylene oxide.
 51. The implant of claim 1, wherein thelipophilic backing layer and/or the hydrophobic coating comprise 1, 2,or all of stearic acid, glyceryl behenate, and/or chitosan.
 52. Theimplant of claim 1, wherein the lipophilic backing layer and thehydrophobic coating are made of the same or essentially the samecompounds or mixture of compounds.
 53. The implant of claim 52, whereinthe lipophilic backing layer and the hydrophobic coating together form asubstantially homogenous hydrophobic layer.
 54. The implant of claim 1,wherein the lipophilic backing layer and the hydrophobic coatingcomprise different compounds.
 55. The implant of claim 1, wherein thehydrophobic coating consists of or consists essentially of glycerylbehenate.
 56. The implant of claim 1, wherein the hydrophobic coatingfurther comprises stearic acid, palmitic acid, cholesterol, or chitosan.57. The implant of claim 1, wherein the drug-containing layer comprisesglyceryl behenate and/or stearic acid, in combination withpolyanhydroglucuronic acid and/or polyethylene oxide.
 58. The implant ofclaim 57, wherein the drug-containing layer comprises glyceryl behenate,stearic acid, and polyethylene oxide.
 59. The implant of claim 57,wherein the drug-containing layer further comprises lipase, cholesterol,glyceryl tristearate, and/or poloxamer F-68.
 60. The implant of claim59, wherein layer c) and/or layer b) contain lipase.
 61. The implant ofclaim 1, wherein the drug-containing layer comprises polyethylene oxideor polyanhydroglucoronic acid.
 62. The implant of claim 61, wherein thedrug-containing layer comprises polyethylene oxide, glycerol behenate,and/or cholesterol.
 63. The implant of claim 1, wherein thedrug-containing layer further comprises stearic acid, lipase,cholesterol, glyceryl tristearate, poloxamer F-68, and/orpolyanhydroglucuronic acid.
 64. The implant of claim 1, wherein thehydrophilic polymer is a polyethylene oxide, a polysaccharide, aprotein, an oxidized cellulose polymer, polyanhydroglucuronic acid, apoloxomer, chitosan, or providone (PVP).
 65. The implant of claim 1,wherein the implant further comprises lipase.
 66. The implant of claim1, wherein the implant is configured for insertion into a resectioncavity.
 67. The implant of claim 1, wherein the implant has been curedat temperatures of at least about 40° C., 45° C., 50° C., 55° C., 60°C., 65° C., 70° C., 75° C., 80° C., 85° C., 90° C., 95° C., 100° C., orup to 200° C.
 68. The implant of claim 1, wherein the implant has beensterilized by gamma radiation, ethylene oxide, or electron beamradiation.
 69. The implant of claim 1, wherein the implant or wafer hasbeen processed by compression, hot-melt extrusion, injection molding,dry powder coating, dipping, coating, spraying, hot-melt granulation,casting, an evaporation technology, or any combination thereof.
 70. Theimplant of claim 1, wherein the implant comprises: 0.1-50% of the drug,5-95% of glyceryl behenate, and about 3-50% of the hydrophilic polymeror pore forming agent.
 71. The implant of claim 1, wherein the implantis further defined as a bilayered implant or wafer.
 72. The implant ofclaim 1, wherein the implant is further defined as a trilayered implantor wafer.
 73. The implant of claim 1, wherein the implant allows forrelease of the drug over a period of at least 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, or 30 or more days, or at least 1, 2, 3, 4, 5, or 6 weeks, or anyrange derivable therein.
 74. The implant of claim 1, wherein the implantfurther comprises a surfactant, a carbohydrate, a polyol, a protein, apeptide, and/or an excipient.
 75. A method of treating a disease ortraumatic injury in a mammalian subject, comprising administering into aresection cavity in the subject the implant of claim 1, wherein the drugelution surface is positioned proximal to the resection cavity, and, thefurther layer or layers comprising the lipophilic backing layer and/orthe hydrophobic coating are positioned distal and/or lateral to the drugelution surface.
 76. (canceled)
 77. The method of claim 75, wherein themammal is a human.
 78. The method of claim 77, wherein the resectioncavity is in the brain of the subject. 79-81. (canceled)
 82. The methodof claim 78, further comprising removing part or all of a tumor from thesubject via the resection cavity.
 83. The method of claim 82, whereinthe tumor is cancerous.
 84. The method of claim 83, wherein the tumor isa brain tumor.
 85. The method of claim 84, wherein the brain tumor is aglioblastoma or glioblastoma multiforme. 86-87. (canceled)
 88. Themethod of claim 75, wherein the surface of the resection cavity or atleast of the part the resection cavity is filled with a surgical glue ora fibrin glue. 89-91. (canceled)
 92. The implant of claim 1, whereindrug is paclitaxel, and wherein layer a) comprises dexamethasone.